RESUMO
IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Complemento C3/imunologia , Glomerulonefrite por IGA/patologia , Glomerulonefrite/patologia , Imunoglobulina A/imunologia , Albuminúria/imunologia , Albuminúria/patologia , Animais , Modelos Animais de Doenças , Glomerulonefrite/imunologia , Glomerulonefrite por IGA/imunologia , Hematúria/imunologia , Hematúria/patologia , Humanos , Imunoglobulina G/imunologia , Rim/imunologia , Rim/patologia , Glomérulos Renais/imunologia , Glomérulos Renais/patologia , Masculino , Células Mesangiais/imunologia , Ratos , Ratos Wistar , Proteínas RecombinantesRESUMO
Autophagy is an important biology process, central to the maintenance of biology process in both physiological and pathological situations. It is regarded as a "double-edged sword"-exerting both protective and/or detrimental effects. These two-way effects are observed in immune cells as well as renal resident cells, including podocytes, mesangial cells, tubular epithelial cells, and endothelial cells of the glomerular capillaries. Mounting evidence suggests that autophagy is implicated in the pathological process of various immune-related renal diseases (IRRDs) as well as the kidney that underwent transplantation. Here, we provide an overview of the pathological role of autophagy in IRRDs, including lupus nephritis, IgA nephropathy, membrane nephropathy, ANCA-associated nephritis, and diabetic nephropathy. The understanding of the pathogenesis and regulatory mechanisms of autophagy in these renal diseases may lead to the identification of new diagnostic targets and refined therapeutic modulation.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas Relacionadas à Autofagia/imunologia , Autofagia/imunologia , Nefropatias Diabéticas/imunologia , Glomerulonefrite por IGA/imunologia , Hematúria/imunologia , Nefrite Lúpica/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Anticorpos Anticitoplasma de Neutrófilos/biossíntese , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Linfócitos B/imunologia , Linfócitos B/patologia , Células Dendríticas , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Glomerulonefrite por IGA/genética , Glomerulonefrite por IGA/patologia , Hematúria/genética , Hematúria/patologia , Humanos , Transplante de Rim , Nefrite Lúpica/genética , Nefrite Lúpica/patologia , Macrófagos/imunologia , Macrófagos/patologia , Células Mesangiais/imunologia , Células Mesangiais/patologia , Podócitos/imunologia , Podócitos/patologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
BACKGROUND: Pauci-immune glomerulonephritis (PIGN) is a major prognostic factor in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV). Renal remission is usually defined as improvement or stabilization of serum creatinine and proteinuria levels but the significance of hematuria is unclear. We evaluated the prognostic value of microscopic hematuria in patients in remission from a first flare of PIGN. METHODS: A multicenter retrospective study was conducted of all patients with histologically proven PIGN in northern France who presented a first renal flare of AAV between 2003 and 2013. All patients received conventional induction treatment and were considered in remission. Two groups were defined by the presence (H+) or absence (H-) of hematuria (dipstick 1+ and/or cytology ≥10,000 erythrocytes/mL). The primary outcome measure was the occurrence of renal relapse (RR) and/or end-stage renal disease (ESRD). RESULTS: Eighty-six patients were included: 41 (48%) had hematuria at remission. The median follow-up time was 44 ± 34 months. There was no significant difference between the groups in terms of the primary endpoint or the number of RR. However, the survival rate without RR was significantly lower in the H+ group (p = 0.002). In multivariate analysis, risk factors for RR were hematuria at remission for relapses within 44 months (hazard ratio [HR] 4.15; 95% CI 1.15-15.01; p = 0.03) and the duration of maintenance immunosuppressive therapy (HR 0.96 per additional month; 95% CI 0.94-0.99; p = 0.002). CONCLUSION: Hematuria at remission after a first PIGN flare was not associated with ESRD but with the occurrence of RR within 44 months of remission.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Glomerulonefrite/tratamento farmacológico , Hematúria/epidemiologia , Imunossupressores/uso terapêutico , Falência Renal Crônica/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Progressão da Doença , Feminino , Seguimentos , França/epidemiologia , Glomerulonefrite/complicações , Glomerulonefrite/imunologia , Glomerulonefrite/mortalidade , Hematúria/diagnóstico , Hematúria/imunologia , Hematúria/urina , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/imunologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Sistema de Registros/estatística & dados numéricos , Indução de Remissão/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
Immunoglobulin A nephropathy (IgAN) is characterized by mesangial IgA and IgG co-deposition. As the clinical course of IgAN is highly variable, a lot of patients will eventually develop to end-stage renal disease (ESRD) within years. Hirudin, a potent and specific thrombin inhibitor, has been reported to treat IgAN with hematuria, but the mechanism is unclear. Our study aims to explore the potential of hirudin and the underlying mechanism in the treatment of IgAN. The establishment of IgAN model was set up in rats through oral and intravenous immunization with bovine gamma-globulin (BGG). Results suggested that hirudin could reduce the increased level of proteinuria, serum creatinine and urea nitrogen in IgAN models. Besides that, hirudin ameliorated the elevated number of apoptotic bodies and expressions of apoptosis-related proteins (caspase-3 and caspase-9) in IgAN model. The fibrosis indexes (transforming growth factor ß-1 (TGF-ß1), Collagen-IV (CoI-IV) and Fibronectin-1) of kidney were remarkably suppressed in IgAN rats treated with hirudin compared with IgAN rats with no further treatment. IgAN rats exhibited remarkably increased inflammatory factors (IL-1ß, IL-6, and IL-18), while hirudin treatment significantly alleviated these alterations. Moreover, the reduced levels of CD4+CD25+Foxp3+ Treg and CD4+IFN-γ+ Th1/CD4+IL-4+ Th2 could be reversed by hirudin in IgAN model. Furthermore, in the process of IgAN, hirudin could inactivate various pathways (IκBα, NF-κB, TNF-α, and VCAM-1) compared with IgAN model group. Taken together, our study indicated that hirudin could ameliorate IgAN through suppressing fibrosis and inflammatory response. These findings provide a new therapeutic method to treat IgAN.
Assuntos
Antitrombinas/farmacologia , Glomerulonefrite por IGA/tratamento farmacológico , Terapia com Hirudina/métodos , Hirudinas/farmacologia , Rim/patologia , Animais , Antitrombinas/uso terapêutico , Creatinina/sangue , Modelos Animais de Doenças , Fibrose , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/imunologia , Glomerulonefrite por IGA/urina , Hematúria/sangue , Hematúria/tratamento farmacológico , Hematúria/imunologia , Hematúria/urina , Humanos , Rim/efeitos dos fármacos , Masculino , Proteinúria/sangue , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Proteinúria/urina , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Resultado do Tratamento , gama-Globulinas/imunologiaRESUMO
Posttransplant glomerulonephritis is a complication of kidney transplant that can impair graft function and long-term graft survival. De novo immunoglobulin A disease in kidney allografts appears to be much less common than the recurrent disease, and in most cases it is diagnosed in protocol biopsies with no clinical evidence of disease or in association with other renal transplant pathologies such as chronic rejection. We present a case of de novo immunoglobulin A nephropathy presenting with overt proteinuria, microscopic hematuria, and progressive deterioration of renal function 30 months after renal transplant.
Assuntos
Glomerulonefrite por IGA/imunologia , Imunoglobulina A/análise , Transplante de Rim/efeitos adversos , Rim/imunologia , Proteinúria/imunologia , Progressão da Doença , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/terapia , Hematúria/imunologia , Hematúria/fisiopatologia , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteinúria/fisiopatologia , Resultado do TratamentoRESUMO
IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. IgAN is characterized by mesangial deposits of IgA1-containing immune complexes. IgA1 usually co-deposits with complement C3 and variable IgG and/or IgM. Exactly 50 years have passed since IgAN was described, however, the pathogenesis of disease onset and progression have not been fully clarified. Animal models can re-create the complex immunologic microenvironments that foster human autoimmunity and nephritis and provide access to tissue compartments not readily examined in patients. Thus, multiple models that may be helpful in studies of specific aspects of IgAN have been developed. A unique spontaneous animal model of IgAN, the ddY mouse, was reported in 1985. These mice show mild proteinuria and glomerular IgA deposits, with a highly variable incidence and degree of glomerular injury owing to a heterogeneous genetic background. Thus, we intercrossed an early onset group of ddY mice in which the development of IgAN resulted in the establishment of a novel 100% early onset-grouped ddY mouse model with increased levels of aberrantly glycosylated IgA and immune complexes. Although the molecular features of human IgA1 are different from rodent IgA, human IgA1 knock-in (α1KI)-CD89 transgenic mice, which express both human IgA1 and CD89, show circulating and mesangial deposits of IgA1-soluble CD89 complexes that result in kidney inflammation, hematuria, and proteinuria. In this review, we introduce several murine models of IgAN that can be useful tools for the analysis of multiple aspects of the pathogenesis of IgAN, which may aid in the assessment of approaches for the treatment of IgAN.
Assuntos
Antígenos CD/genética , Modelos Animais de Doenças , Glomerulonefrite por IGA/genética , Imunoglobulina A/genética , Camundongos , Receptores Fc/genética , Animais , Fator Ativador de Células B/genética , Fator Ativador de Células B/imunologia , Galactose/metabolismo , Técnicas de Introdução de Genes , Glomerulonefrite por IGA/imunologia , Glicosilação , Hematúria/genética , Hematúria/imunologia , Humanos , Imunoglobulina A/metabolismo , Lactalbumina/imunologia , Camundongos Endogâmicos , Camundongos Knockout , Camundongos Transgênicos , Fator 88 de Diferenciação Mieloide/imunologia , Nefrite/genética , Nefrite/imunologia , Proteinúria/genética , Proteinúria/imunologia , Receptores Fc/imunologia , Vírus Sendai/imunologia , Receptor Toll-Like 9/imunologia , Tricotecenos/imunologia , Uteroglobina/genéticaRESUMO
Although activation of mouse natural killer T (NKT) cells by α-galactosylceramide (α-GalCer) causes failure of multiple organs, including the kidneys, the precise mechanisms underlying kidney injury remain unclear. Here, we showed that α-GalCer-activated mouse NKT cells injured both kidney vascular endothelial cells and tubular epithelial cells in vitro, causing acute kidney injury (AKI) with hematuria in middle-aged mice. The perforin-mediated pathway was mainly involved in glomerular endothelial cell injury, whereas the TNF-α/Fas ligand pathway played an important role in the injury of tubular epithelial cells. Kidney injury in young mice was mild but could be significantly exacerbated if NKT cells were strongly activated by NK cell depletion alone or in combination with IL-12 pretreatment. When stimulated by a combination of IL-2 and IL-12, human CD56+ T cells, a functional counterpart of mouse NKT cells, also damaged both glomerular endothelial cells and tubular epithelial cells, with the former being affected in a perforin-dependent manner. These data suggest that both mouse NKT cells and human CD56+ T cells are integral to the processes that mediate AKI. Targeting CD56+ T cells may, therefore, be a promising approach to treat AKI.
Assuntos
Injúria Renal Aguda/imunologia , Antígeno CD56/imunologia , Citotoxicidade Imunológica , Hematúria/imunologia , Túbulos Renais Proximais/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Fatores Etários , Animais , Antígeno CD56/metabolismo , Linhagem Celular , Técnicas de Cocultura , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Proteína Ligante Fas/metabolismo , Feminino , Galactosilceramidas , Hematúria/induzido quimicamente , Hematúria/metabolismo , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo , Fenótipo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Fatores Sexuais , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Immunoglobulin A nephropathy (IgAN) is the most commonly occurring glomerulonephritis. Recurrence of disease in the transplanted kidney can significantly reduce allograft survival rates. Currently, there is no definitive management plan for IgAN recurrence in a transplant that reduces the rate of decline of allograft function and prolongs time to dialysis or re-transplantation. Herein we present a 48-year-old man who had received a renal transplantation in 2006 following his diagnosis of IgAN. In 2015, the patient was noted to have an elevated blood pressure and proteinuria (urinary protein:creatinine ratio [uPCR] 170 mg/mmol). A transplant biopsy confirmed recurrent IgAN. A year later, he presented with dipstick hematuria, nephrotic-range proteinuria (uPCR 820 mg/mmol), and a serum creatinine of 90 to 140 µmol/L. A second biopsy revealed mesangioproliferative glomerulopathy consistent with crescentic IgAN. An optimal management plan is currently unknown for recurrent crescentic IgAN in the transplanted kidney. We decided to treat this patient with oral cyclophosphamide daily and high-dose prednisolone. The treatment has so far yielded a positive response and managed to preserve allograft function without significant adverse effects for our patient. Our case illustrates the importance of timely biopsies to identify recurrence of disease and highlights an effective therapeutic option for recurrent IgAN with crescent formation in a transplant.
Assuntos
Ciclofosfamida/administração & dosagem , Glomerulonefrite por IGA/tratamento farmacológico , Imunossupressores/administração & dosagem , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Biópsia , Glomerulonefrite por IGA/cirurgia , Hematúria/imunologia , Humanos , Rim/imunologia , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/imunologia , Proteinúria/imunologia , RecidivaRESUMO
BACKGROUND AND OBJECTIVES: The significance of persistent hematuria or proteinuria in patients with ANCA-associated vasculitis who are otherwise in clinical remission is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A post hoc analysis was conducted using participants enrolled in two randomized, placebo-controlled clinical trials who had active GN due to ANCA-associated vasculitis, had positive ANCA, and achieved remission by month 6. Dipstick and microscopic urinalyses were performed at each visit. Persistent hematuria or proteinuria for at least 6 months and the cumulative duration of hematuria were examined. Renal relapse was defined as new or worsening red blood cell casts and/or worsening kidney function according to the Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis. RESULTS: There were 149 patients included in this study: 42% had persistent hematuria, and 43% had persistent proteinuria beyond 6 months. Persistent hematuria was associated with a significantly higher risk of relapse, even after adjusting for potential confounders (subdistribution hazard ratio, 3.99; 95% confidence interval, 1.20 to 13.25; P=0.02); persistent proteinuria was not associated with renal relapse (subdistribution hazard ratio, 1.44; 95% confidence interval, 0.47 to 4.42; P=0.53). Furthermore, greater cumulative duration of hematuria was significantly associated with a higher risk of renal relapse (adjusted subdistribution hazard ratio, 1.08 per each month; 95% confidence interval, 1.03 to 1.12; P<0.01). The median time to renal relapse was 22 months. CONCLUSIONS: In patients with ANCA-associated vasculitis and kidney involvement who achieve remission after induction therapy, the presence of persistent hematuria, but not proteinuria, is a significant predictor of future renal relapse.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/urina , Glomerulonefrite/urina , Hematúria/urina , Proteinúria/urina , Urinálise , Adulto , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Biomarcadores/urina , Progressão da Doença , Etanercepte/uso terapêutico , Feminino , Glomerulonefrite/diagnóstico , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Hematúria/diagnóstico , Hematúria/tratamento farmacológico , Hematúria/imunologia , Humanos , Imunossupressores/uso terapêutico , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/imunologia , Falência Renal Crônica/urina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Proteinúria/diagnóstico , Proteinúria/tratamento farmacológico , Proteinúria/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fitas Reagentes , Recidiva , Indução de Remissão , Medição de Risco , Fatores de Risco , Rituximab/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Urinálise/instrumentaçãoRESUMO
Although tonsillectomy are used as therapeutic options to prevent chronic renal failure in IgA nephropathy (IgAN) patients, the relationship between IgAN and tonsils is not fully proved by basic research. Recently, circulating CX3CR1-positive cells were reportedly involved in promoting hematuria in patients with IgAN. In this study, we focused on the expression of CX3CR1 in tonsillar mononuclear cells in IgAN patients. Immunohistological analysis revealed greater distribution of CX3CR1-positive cells in the inter-follicular area of tonsils in IgAN patients than in non-IgAN patients. CX3CR1-positive cells were also found in the affected renal glomerulus of IgAN patients. Flow cytometric analysis revealed the expression of CX3CR1 on tonsillar CD8-positive cells to be significantly higher in IgAN patients. CpG-oligodeoxynucleotides enhanced the expression in IgAN patients. The chemotactic response of tonsillar mononuclear cells to fractalkine was significantly higher in IgAN patients. Expression of CX3CR1 on peripheral blood CD8-positive cells in IgAN patients was significantly higher, and decreased after tonsillectomy, along with the disappearance of hematuria. These results suggest that hyper-immune response to microbial DNA enhanced the expression of CX3CR1 on tonsillar CD8-positive cells in IgAN patients, followed by the migration of the cells to renal lesions via blood circulation, resulting in the development of hematuria.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Glomerulonefrite por IGA/diagnóstico , Hematúria/diagnóstico , Tonsila Palatina/patologia , Receptores de Quimiocinas/metabolismo , Adolescente , Adulto , Receptor 1 de Quimiocina CX3C , Quimiocina CX3CL1/imunologia , Feminino , Glomerulonefrite por IGA/imunologia , Hematúria/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Quimiocinas/genética , Tonsilectomia , Regulação para Cima , Adulto JovemRESUMO
OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) is considered "pauci-immune" with absent or mild glomerular tuft staining for immunoglobulin (Ig) and/or complement. However, it is not unusual to see some immune deposits (ID) within glomeruli on immunofluorescence (IF). We determined to evaluate the prevalence and clinical significance of immune deposits in ANCA-associated GN. METHODS: We included all patients with ANCA associated vasculitis with renal biopsies between January 2002 and May 2014: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis and renal limited vasculitis. Patients were divided into Group A: biopsy without ID (≤2+ intensity of immunostaining) and Group B: biopsy with ID (>2+ intensity of immunostaining). Serum creatinine, estimated glomerular filtration rate (eGFR) at time of the biopsy, amount of proteinuria and hematuria, requirement of dialysis and extra renal involvement were recorded. RESULTS: Fifty-three patients (75.4% females) were included. Mean age at biopsy was 66.3 years. Typical pauci-immune GN was found in 39 patients (73.5%, group A). In 14 patients (26.4%, group B) examination revealed substantial deposition of Ig or complement in the mesangium and/or along the glomerular capillary wall. The only difference comparing both groups was significantly higher proteinuria in group B (mean 1.6/24 h (SD: 10.7) vs. 0.8/24 h (SD: 7.6), p=0.0036). CONCLUSIONS: In ANCA GN at least a quarter of patients were not "pauci-immune" (26.4%). In this subgroup, immune deposits were only associated with a significantly higher proteinuria. Further basic and clinical research is needed to elucidate the significance of immune deposition in ANCA GN.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Proteínas do Sistema Complemento/análise , Glomerulonefrite/imunologia , Imunoglobulina G/análise , Glomérulos Renais/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Argentina/epidemiologia , Biomarcadores/sangue , Biópsia , Creatinina/sangue , Feminino , Imunofluorescência , Taxa de Filtração Glomerular , Glomerulonefrite/diagnóstico , Glomerulonefrite/epidemiologia , Glomerulonefrite/fisiopatologia , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/imunologia , Hematúria/diagnóstico , Hematúria/epidemiologia , Hematúria/imunologia , Humanos , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Masculino , Poliangiite Microscópica/diagnóstico , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/imunologia , Prevalência , Proteinúria/diagnóstico , Proteinúria/epidemiologia , Proteinúria/imunologia , Estudos RetrospectivosRESUMO
BACKGROUND: Clinicopathological significance of monoclonal IgA deposition and its relation to bone marrow abnormalities in IgA nephropathy (IgAN) remains unclear. METHODS: We retrospectively investigated the prevalence and clinicopathological significance of monoclonal IgA deposition in 65 patients with IgAN. Serum-free light chain ratio, and urinary Bence Jones protein were also measured. RESULTS: Thirty-nine percent of patients were men, median age was 40 and median observation period was 31 months. Five patients (Group M) showed monoclonal IgA lambda deposition and one showed monoclonal IgA kappa deposition. Fifty-nine patients (Group P) showed polyclonal IgA deposition. There were no significant differences in the degree of proteinuria, hematuria and renal function between Group M and Group P. Total protein and albumin were significantly lower in Group M than in Group P. According to the Oxford classification, the percentage of patients with M1 was significantly higher in Group M than in Group P. One patient in Group P showed serum monoclonal IgG lambda. No patient showed abnormal serum-free light chain ratio. Seventy-five percent in Group M and 42 % in Group P were treated with steroid. Three patients in Group P progressed to end-stage renal disease (ESRD). The frequency of disappearance of proteinuria or hematuria and progression to ESRD was not different between the groups. CONCLUSIONS: The prevalence of monoclonal IgA deposition was 9.2 %. Although some parameters differed between the groups, renal outcome were similar. Thus, IgAN with monoclonal IgA deposition seems not to be different entity from those with polyclonal IgA deposition.
Assuntos
Anticorpos Monoclonais/análise , Glomerulonefrite por IGA/imunologia , Imunoglobulina A/análise , Cadeias kappa de Imunoglobulina/análise , Cadeias lambda de Imunoglobulina/análise , Rim/imunologia , Adolescente , Adulto , Idoso , Proteína de Bence Jones/urina , Biópsia , Progressão da Doença , Feminino , Imunofluorescência , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/terapia , Hematúria/imunologia , Humanos , Rim/fisiopatologia , Rim/ultraestrutura , Falência Renal Crônica/imunologia , Masculino , Pessoa de Meia-Idade , Proteinúria/imunologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Urinálise , Adulto JovemRESUMO
We present a case of a 71-year-old woman who initially presented with renal-limited antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Following standard therapy with cyclophosphamide, steroids and plasma exchange, her renal function began to improve. However, despite appropriate treatment, her renal function subsequently deteriorated and she suffered haemoptysis. Owing to diagnostic uncertainty, bronchoscopy and a repeat renal biopsy were performed. The bronchoscopy washings demonstrated positivity for cytomegalovirus (CMV) DNA, and in combination with a positive serum CMV PCR, immunosuppression was withheld. Treatment with ganciclovir was started. Repeat renal biopsy demonstrated active vasculitis and, following successful treatment of CMV disease, immunosuppression was re-started alongside prophylactic valganciclovir. This resulted in a successful outcome for the patient. Pulmonary CMV disease may mimic pulmonary disease associated with vasculitis, posing a diagnostic challenge to clinicians. We recommend a low threshold when testing for CMV in these patients.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/terapia , Infecções por Citomegalovirus/etiologia , Imunossupressores/efeitos adversos , Nefropatias/etiologia , Nefropatias/terapia , Pneumonia Viral/etiologia , Corticosteroides/efeitos adversos , Idoso , Antivirais/uso terapêutico , Broncoscopia , Ciclofosfamida/efeitos adversos , Citomegalovirus/genética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/prevenção & controle , DNA Viral , Feminino , Ganciclovir/análogos & derivados , Ganciclovir/uso terapêutico , Hematúria/etiologia , Hematúria/imunologia , Hemoptise/etiologia , Hemoptise/imunologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Quimioterapia de Indução , Nefropatias/imunologia , Troca Plasmática , Pneumonia Viral/imunologia , Proteinúria/etiologia , Proteinúria/imunologia , ValganciclovirRESUMO
C1q nephropathy (C1qN) is defined by conspicuous C1q deposits in the glomerular mesangial regions of patients who do not have any evidence of systemic lupus erythematosus (SLE). We present our experience with C1qN over the last three years. In total, 1775 native renal biopsies were reviewed and dominant/co-dominant C1q mesangial deposits in patients with absence of clinical and/or serological evidence of SLE were considered as C1qN. Their clinical profile and renal function status were studied and correlated. C1qN was observed in 11 patients (0.61%), and included eight males and three females; the mean age was 36.6 years. The most common presentation was nephrotic syndrome. Hematuria was noted in eight patients (72%). The mean serum creatinine was 2.78 mg/dL. Hypertension was seen in two patients (18%). Mesangial proliferative glomerulonephritis (MePGN) was the most common histological pattern, followed by focal and segmental glomerulosclerosis and other lesions. The common codeposits along with C1q were IgM, followed by C3 and others. MePGN had better prognosis than others. To conclude, C1qN was noted in 0.61% of all renal biopsies with bimodal age distribution and may present as podocytopathy or non-podocytopathy. The prognosis depends on the morphological pattern and C1q deposits per se are not prognostic indicators.
Assuntos
Complemento C1q/análise , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulosclerose Segmentar e Focal/imunologia , Glomérulos Renais/imunologia , Adolescente , Adulto , Idoso , Biomarcadores/análise , Biomarcadores/sangue , Biópsia , Criança , Complemento C3/análise , Creatinina/sangue , Feminino , Imunofluorescência , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/epidemiologia , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/epidemiologia , Hematúria/diagnóstico , Hematúria/epidemiologia , Hematúria/imunologia , Humanos , Imunoglobulina M/análise , Índia/epidemiologia , Glomérulos Renais/patologia , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/epidemiologia , Síndrome Nefrótica/imunologia , Valor Preditivo dos Testes , Prognóstico , Fatores de Tempo , Adulto JovemRESUMO
Therapy for BK virus (BKV)-associated hemorrhagic cystitis (BKV-HC) is limited after hematopoietic stem cell transplantation (HSCT). We examined whether choreito, a formula from Japanese traditional Kampo medicine, is effective for treating BKV-HC. Among children who underwent allogeneic HSCT between October 2006 and March 2014, 14 were diagnosed with BKV-HC (median, 36 days; range, 14 to 330 days) after HSCT, and 6 consecutive children received pharmaceutical-grade choreito extract granules. The hematuria grade before treatment was significantly higher in the choreito group than in the nonchoreito group (P = .018). The duration from therapy to complete resolution was significantly shorter in the choreito group (median, 9 days; range, 4 to 17 days) than in the nonchoreito group (median, 17 days; range, 15 to 66 days; P = .037). In 11 children with macroscopic hematuria, the duration from treatment to resolution of macroscopic hematuria was significantly shorter in the choreito group than in the nonchoreito group (median, 2 days versus 11 days; P = .0043). The BKV load in urine was significantly decreased 1 month after choreito administration. No adverse effects related to choreito administration were observed. Choreito may be a safe and considerably promising therapy for the hemostasis of BKV-HC after HSCT.
Assuntos
Antivirais/uso terapêutico , Cistite/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Hematúria/tratamento farmacológico , Infecções Tumorais por Vírus/tratamento farmacológico , Viremia/tratamento farmacológico , Adolescente , Vírus BK/efeitos dos fármacos , Vírus BK/imunologia , Criança , Cistite/imunologia , Cistite/patologia , Cistite/virologia , DNA Viral/antagonistas & inibidores , DNA Viral/urina , Feminino , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virologia , Hematúria/imunologia , Hematúria/patologia , Hematúria/virologia , Humanos , Japão , Masculino , Medicina Tradicional do Leste Asiático , Estudos Retrospectivos , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Infecções Tumorais por Vírus/imunologia , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia , Carga Viral/efeitos dos fármacos , Viremia/imunologia , Viremia/patologia , Viremia/virologiaRESUMO
BACKGROUND: Hematuria is the first manifestation of urinary abnormality in immunoglobulin A nephropathy (IgAN). Hematuria has recently been reported as a risk factor for deterioration of renal function; however, its cause remains unknown. METHODS: We analyzed the surface marker of peripheral blood mononuclear cells before and immediately after tonsillectomy in IgAN patients and controls (chronic tonsillitis or tonsillar hypertrophy) by flow cytometry and investigated the association with hematuria. To prove our hypothesis that NK cells induce hematuria, we administered IL-12, activator of NK cells, to HIGA mice. In addition, we transferred cultured NK cells to nude rats and transferred the CD16(+)CD56(+) cells, including NK cells, that are derived from the peripheral blood of IgAN patients immediately after tonsillectomy to nude rats to assess the hematuria level and renal histology of the recipients. We also performed cytotoxicity assays against glomerular endothelial cells by NK cells. RESULTS: We found that IgAN patients who showed rapid deterioration of hematuria after tonsillectomy also displayed a significant increase in CD16(+)CD56(+) cells in the peripheral blood immediately after tonsillectomy. Exogenous administration of IL-12 to HIGA mice induced hematuria. Adoptive transfer of either cells of an NK cell line, or of CD16(+)CD56(+) cells derived from IgAN patients, into nude rats induced hematuria in the recipients. In vitro analysis showed that NK cells exert cytotoxic activity toward human glomerular endothelial cells in a dose-dependent manner. CONCLUSIONS: CD16(+)CD56(+) cells seem to be responsible for hematuria in IgAN.
Assuntos
Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/complicações , Hematúria/imunologia , Células Matadoras Ativadas por Linfocina/química , Imunidade Adaptativa , Adolescente , Corticosteroides/uso terapêutico , Adulto , Animais , Antígeno CD56/análise , Linhagem Celular , Criança , Testes Imunológicos de Citotoxicidade , Células Endoteliais , Feminino , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Interleucina-12/farmacologia , Células Matadoras Ativadas por Linfocina/efeitos dos fármacos , Células Matadoras Ativadas por Linfocina/transplante , Contagem de Leucócitos , Masculino , Camundongos , Pessoa de Meia-Idade , Período Pós-Operatório , Período Pré-Operatório , Ratos , Receptores de IgG/análise , Tonsilectomia , Tonsilite/complicações , Tonsilite/cirurgia , Adulto JovemAssuntos
Anti-Inflamatórios/uso terapêutico , Cistite/tratamento farmacológico , Hematúria/tratamento farmacológico , Imunossupressores/uso terapêutico , Metilprednisolona/uso terapêutico , Lesões por Radiação/tratamento farmacológico , Óxido de Alumínio/uso terapêutico , Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Sangue , Terapia Combinada , Ciclofosfamida/administração & dosagem , Cistite/etiologia , Cistite/imunologia , Cistite/terapia , Doxorrubicina/administração & dosagem , Estrogênios/uso terapêutico , Etoposídeo/administração & dosagem , Hidratação , Hematúria/etiologia , Hematúria/imunologia , Hematúria/terapia , Humanos , Oxigenoterapia Hiperbárica , Imunossupressores/administração & dosagem , Irradiação Linfática/efeitos adversos , Metástase Linfática/radioterapia , Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/radioterapia , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Lesões por Radiação/etiologia , Lesões por Radiação/imunologia , Radioterapia Conformacional/efeitos adversos , Recidiva , Rituximab , Terapia de Salvação/efeitos adversos , Vincristina/administração & dosagemRESUMO
C3 glomerulopathy is an heterogeneous group of glomerular diseases associated with acquired or genetic abnormalities of complement alternative pathway (AP) components. It is characterized by predominant C3 deposits in the mesangium and along the glomerular basement membrane (GBM). Presenting features comprise proteinuria (sometimes with nephritic syndrome), haematuria, hypertension and renal failure. C3 glomerulopathy have a poor renal prognosis with progression to end stage renal disease (ESRD) in 50% of cases during the first decade after initial presentation. Moreover, C3 deposits recur in most of cases after renal transplantation. Patients frequently have low serum C3 level attributed to the activation of the alternative pathway of complement. Animal models have confirmed the role of excessive C3 activation in the pathogenesis of C3 glomerulopathy. To date, the optimal treatment remains unknown. It is currently based on the use of angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin II-receptor blockers (ARB), sometimes associated with immunosuppressive therapy. Blockade of C5a release with eculizumab, a monoclonal anti-C5 antibody, may be of particular interest in the treatment of C3G.
Assuntos
Complemento C3/metabolismo , Glomerulonefrite Membranoproliferativa/imunologia , Glomerulonefrite Membranoproliferativa/patologia , Biomarcadores/sangue , Progressão da Doença , Medicina Baseada em Evidências , Membrana Basal Glomerular/patologia , Mesângio Glomerular/patologia , Glomerulonefrite Membranoproliferativa/sangue , Glomerulonefrite Membranoproliferativa/terapia , Hematúria/imunologia , Humanos , Hipertensão/imunologia , Fatores Imunológicos/metabolismo , Falência Renal Crônica/imunologia , Prognóstico , Proteinúria/imunologiaRESUMO
INTRODUCTION: There is no data specifically on the clinical and immunopathologic features of Immunoglobulin M nephropathy (IgMN) in adults with kidney diseases in Pakistan. MATERIALS AND METHODS: We retrospectively reviewed our adult native renal biopsy records from May 2001 to April 2010 and identified 57 cases out of a total of 1,753 records labeled as IgMN on final histopathological analysis. Among these, 41 cases were included in the present analysis. Their relevant data items were collected from the case files and biopsy reports. RESULTS: The mean age of this cohort was 30.21 ± 10.12 years. The male-female ratio was 1.15:1. The most common presentation was idiopathic nephrotic syndrome. Hematuria and hypertension at presentation were noted in 24 (58.5%) and 10 (24.4%) patients, respectively. The most common morphologic change was glomerular mesangial cell proliferation, found in 28 biopsies (68.3%). Mesangial matrix expansion was noted in 16 (39%). Minor glomerular alterations were noted in 5 cases (12.2%) and focal segmental glomerulosclerosis in 4 (9.8%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all specimens. Subdominant IgA was noted in 6 cases (14.6%). Complements C3 and C1q were found in 28 (68.3%) and 21 (51.2%) patients, respectively. CONCLUSIONS: Our results show that IgMN is not very common in adults. Its clinicopathological spectrum is similar to that described from the neighboring countries, showing a spectrum of morphologic changes ranging from minor changes to focal segmental glomerulosclerosis.