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1.
Parasite Immunol ; 42(8): e12730, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32403171

RESUMO

Proliferative kidney disease (PKD), caused by the myxozoan Tetracapsuloides bryosalmonae, is one of the most serious parasitic diseases of salmonids in which outbreaks cause severe economic constraints for the aquaculture industry and declines of wild species throughout Europe and North America. Given that rainbow trout (Oncorhynchus mykiss) is one of the most widely farmed freshwater fish and an important model species for fish immunology, most of the knowledge on how the fish immune response is affected during PKD is from this organism. Once rainbow trout are infected, PKD pathogenesis results in a chronic kidney immunopathology mediated by decreasing myeloid cells and increasing lymphocytes. Transcriptional studies have revealed the regulation of essential genes related to T-helper (Th)-like functions and a dysregulated B-cell antibody type response. Recent reports have discovered unique details of teleost B-cell differentiation and functionality and characterized the differential immunoglobulin (Ig)-mediated response. These studies have solidified the rainbow trout T. bryosalmonae system as a sophisticated disease model capable of feeding key advances into mainstream immunology and have contributed essential information to design novel parasite disease prevention strategies. In our following perspective, we summarize these efforts to evaluate the immune mechanisms of rainbow trout during PKD pathogenesis.


Assuntos
Nefropatias/imunologia , Nefropatias/parasitologia , Myxozoa/imunologia , Oncorhynchus mykiss/imunologia , Doenças Parasitárias em Animais/imunologia , Animais , Linfócitos B/imunologia , Doenças dos Peixes/imunologia , Imunoglobulina D/imunologia , Imunoglobulina M/imunologia , Imunoglobulinas/imunologia , Ativação Linfocitária/imunologia , Myxozoa/genética , Myxozoa/fisiologia , Oncorhynchus mykiss/parasitologia , Doenças Parasitárias em Animais/parasitologia , Linfócitos T Auxiliares-Indutores/imunologia
2.
Nephrol Dial Transplant ; 35(6): 920-925, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32445573

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has created major challenges for all countries around the globe. Retrospective studies have identified hypertension, cardiovascular disease, diabetes and older age as risk factors for high morbidity and mortality from COVID-19. There is a general concern that patients with immune-mediated kidney diseases, namely those on immunosuppressive therapies and/or those with more advanced kidney failure, could particularly be at risk for adverse outcomes due to a compromised antiviral immunity. Uncertainties exist on how management routines should be reorganized to minimize the risk of severe acute respiratory syndrome coronavirus 2 infection and what measures are necessary for infected patients. The aim of the present review of the Immunonephrology Working Group of the European Renal Association-European Dialysis and Transplant Association is to provide recommendations for the management of patients with immune-mediated kidney diseases based on the available evidence, similar circumstances with other infectious organisms and expert opinions from across Europe. Such recommendations may help to minimize the risk of encountering COVID-19 or developing complications during COVID-19 in patients with immune-mediated kidney disease.


Assuntos
Infecções por Coronavirus/imunologia , Infecções por Coronavirus/terapia , Nefropatias/imunologia , Nefropatias/terapia , Nefrologia/normas , Pneumonia Viral/imunologia , Pneumonia Viral/terapia , Antivirais , Betacoronavirus , Infecções por Coronavirus/complicações , Europa (Continente) , Humanos , Imunossupressores/uso terapêutico , Nefropatias/complicações , Pandemias , Pneumonia Viral/complicações , Diálise Renal , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sociedades Médicas
3.
Pathologe ; 41(3): 238-247, 2020 May.
Artigo em Alemão | MEDLINE | ID: mdl-32240352

RESUMO

Increasing interest in the role of the complement system in systemic and renal disease is based on new pathophysiological and therapeutic insights of the recent past and particularly in genetic analyses in children with atypical hemolytic uremic syndrome (aHUS). aHUS is the prototypical systemic disease associated with excessive activation of the alternative complement pathway and manifests in the kidney, but also in other organs as thrombotic microangiopathy (TMA). Pathomechanisms discovered to induce the overactivation of the alternative complement pathway in aHUS led to the first successful therapeutic application of a C5b9 inhibitor. This suppression of the terminal complement cascade succeeded in inhibiting local tissue damage. Thereafter, thanks to advanced modern technologies, further systemic and renal diseases associated with mutations or auto-antibodies targeting the complement pathway were identified. Hereby, disease onset is frequently associated with an additional trigger, e.g. infection or hormonal alterations/imbalances, against the background of a pre-existing predisposition of the patient.Due to the growing understanding of the regulation, and thus the possibility of therapeutic modulation of the different complement pathways, and due to the increasing availability of a variety of drugs inhibiting the complement system, interest in complement-mediated systemic and renal disease has been steadily increasing, making it a "hot-topic" in medicine in recent years.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/imunologia , Ativação do Complemento , Proteínas do Sistema Complemento/imunologia , Nefropatias/imunologia , Criança , Humanos , Microangiopatias Trombóticas/imunologia
4.
Transplant Proc ; 52(3): 857-864, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32143865

RESUMO

Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.


Assuntos
Nefropatias/etiologia , Transplante de Rim/efeitos adversos , Paraproteinemias/etiologia , Complicações Pós-Operatórias/etiologia , Idoso , Feminino , Humanos , Rim/imunologia , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Paraproteinemias/imunologia , Complicações Pós-Operatórias/imunologia
5.
Nat Immunol ; 21(1): 30-41, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31819254

RESUMO

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.


Assuntos
Lesão Renal Aguda/imunologia , Apolipoproteína C-III/imunologia , Caspase 8/metabolismo , Nefropatias/imunologia , Monócitos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Lesão Renal Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apolipoproteína C-III/genética , Linhagem Celular , Modelos Animais de Doenças , Células HEK293 , Humanos , Inflamassomos/imunologia , Inflamação/genética , Inflamação/imunologia , Nefropatias/patologia , Proteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
6.
Parasit Vectors ; 12(1): 569, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783772

RESUMO

BACKGROUND: Tetracapsuloides bryosalmonae is a myxozoan parasite which causes economically important and emerging proliferative kidney disease (PKD) in salmonids. Brown trout, Salmo trutta is a native fish species of Europe, which acts as asymptomatic carriers for T. bryosalmonae. There is only limited information on the molecular mechanism involved in the kidney of brown trout during T. bryosalmonae development. We employed RNA sequencing (RNA-seq) to investigate the global transcriptome changes in the posterior kidney of brown trout during T. bryosalmonae development. METHODS: Brown trout were exposed to the spores of T. bryosalmonae and posterior kidneys were collected from both exposed and unexposed control fish. cDNA libraries were prepared from the posterior kidney and sequenced. Bioinformatics analysis was performed using standard pipeline of quality control, reference mapping, differential expression analysis, gene ontology, and pathway analysis. Quantitative real time PCR was performed to validate the transcriptional regulation of differentially expressed genes, and their correlation with RNA-seq data was statistically analyzed. RESULTS: Transcriptome analysis identified 1169 differentially expressed genes in the posterior kidney of brown trout, out of which 864 genes (74%) were upregulated and 305 genes (26%) were downregulated. The upregulated genes were associated with the regulation of immune system process, vesicle-mediated transport, leucocyte activation, and transport, whereas the downregulated genes were associated with endopeptidase regulatory activity, phosphatidylcholine biosynthetic process, connective tissue development, and collagen catabolic process. CONCLUSION: To our knowledge, this is the first RNA-seq based transcriptome study performed in the posterior kidney of brown trout during active T. bryosalmonae development. Most of the upregulated genes were associated with the immune system process, whereas the downregulated genes were associated with other metabolic functions. The findings of this study provide insights on the immune responses mounted by the brown trout on the developing parasite, and the host molecular machineries modulated by the parasite for its successful multiplication and release.


Assuntos
Doenças dos Peixes/imunologia , Nefropatias/veterinária , Myxozoa/patogenicidade , Doenças Parasitárias em Animais/imunologia , Truta/parasitologia , Animais , Infecções Assintomáticas , Biologia Computacional , Doenças dos Peixes/parasitologia , Expressão Gênica , Perfilação da Expressão Gênica , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Rim/parasitologia , Nefropatias/imunologia , Nefropatias/parasitologia , Análise de Sequência de RNA , Organismos Livres de Patógenos Específicos , Truta/imunologia
7.
Biomed Res Int ; 2019: 7567638, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828127

RESUMO

Background: Delayed rectifier K+-channel, Kv1.3, is most predominantly expressed in T-lymphocytes and macrophages. In such leukocytes, Kv1.3-channels play pivotal roles in the activation and proliferation of cells, promoting cellular immunity. Since leukocyte-derived cytokines stimulate fibroblasts to produce collagen fibers in inflamed kidneys, Kv1.3-channels expressed in leukocytes would contribute to the progression of tubulointerstitial renal fibrosis. Methods: Male Sprague-Dawley rats that underwent unilateral ureteral obstruction (UUO) were used at 1, 2, or 3 weeks after the operation. We examined the histological features of the kidneys and the leukocyte expression of Kv1.3-channels. We also examined the therapeutic effects of a selective channel inhibitor, margatoxin, on the progression of renal fibrosis and the proliferation of leukocytes within the cortical interstitium. Results: In rat kidneys with UUO, progression of renal fibrosis and the infiltration of leukocytes became most prominent at 3 weeks after the operation, when Kv1.3-channels were overexpressed in proliferating leukocytes. In the cortical interstitium of margatoxin-treated UUO rat kidneys, immunohistochemistry revealed reduced expression of fibrosis markers. Additionally, margatoxin significantly decreased the numbers of leukocytes and suppressed their proliferation. Conclusions: This study clearly demonstrated that the numbers of T-lymphocytes and macrophages were markedly increased in UUO rat kidneys with longer postobstructive days. The overexpression of Kv1.3-channels in leukocytes was thought to be responsible for the proliferation of these cells and the progression of renal fibrosis. This study strongly suggested the therapeutic usefulness of targeting lymphocyte Kv1.3-channels in the treatment of renal fibrosis.


Assuntos
Nefropatias/imunologia , Canal de Potássio Kv1.3/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Obstrução Ureteral/imunologia , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Fibrose , Nefropatias/tratamento farmacológico , Nefropatias/patologia , Macrófagos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Linfócitos T/patologia , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/patologia
8.
Nutrients ; 11(11)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694260

RESUMO

The prevalence of renal and cardiovascular disease (CVD) in patients with systemic lupus erythematosus (SLE) is higher than in general populations. Recently, a causal role of gut microbiota on the development of immune responses in SLE has been described. Probiotic consumption changes the composition of gut microbiota, preventing SLE progression. The aim of this review is to explore the role of the gut microbiota in the development of renal and cardiovascular disease in SLE and how probiotics could be a therapeutic option. Despite strong evidence on the beneficial effects of probiotics in the development of autoimmunity and nephritis in SLE, only a few studies described the protective effects of Lactobacillus in important risk factors for CVD, such as endothelial dysfunction and hypertension in mice. The preventive effects of probiotics in renal and CVD in humans have not been established yet.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Nefropatias/prevenção & controle , Lúpus Eritematoso Sistêmico/microbiologia , Probióticos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Microbioma Gastrointestinal/imunologia , Nefropatias/imunologia , Nefropatias/microbiologia , Lactobacillus , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Fatores de Risco
9.
Toxicol Lett ; 317: 110-119, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618666

RESUMO

Trichloroethylene (TCE), a commonly used industrial solvent and degreasing agent, is known to cause trichloroethylene hypersensitivity syndrome (THS) with multi-system damage, including skin, liver and kidney. Clinical evidence have shown that the kidney injury occurs in THS and our previous studies suggested that the terminal complement complex C5b-9 deposited in impaired renal tubules induced by TCE with unclear mechanisms. In the present study, we questioned whether activation of the complement system with renal deposition of C5b-9 contributes to TCE-induced kidney injury in THS. We established a BALB/c mouse model of TCE sensitization with or without pretreatment of exogenous CD59, a C5b-9 inhibitory protein. H&E staining, PAS staining, and biochemical detection of urinary proteins were performed to assess renal function. Deposition of C5b-9 and expression of CD59 were evaluated by immunohistochemistry. Sub-lytic effects of C5b-9 in tubular epithelial cells were assessed by lactate dehydrogenase (LDH) cytotoxicity assay. Expression of endocytosis receptors megalin and cubilin on proximal tubules were assessed by immunofluorescence and qRT-PCR. We found that TCE sensitization induced structural and functional changes of renal tubules in mice, associated with the deposition of sub-lytic C5b-9 on proximal tubular epithelial cells. TCE sensitization decreased proximal tubule uptake of filtered proteins and renal expression of megalin and cubilin, phenotypes that were attenuated by pretreatment with exogenous CD59. Overall, our findings reveal a novel mechanism underlying sub-lytic C5b-9 acting on megalin and cubilin, contributes to the renal tubules damage by TCE exposure.


Assuntos
Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Endocitose , Hipersensibilidade/metabolismo , Nefropatias/metabolismo , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Receptores de Superfície Celular/metabolismo , Tricloroetileno , Animais , Células Cultivadas , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade/imunologia , Hipersensibilidade/patologia , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Nefropatias/patologia , Túbulos Renais Proximais/imunologia , Túbulos Renais Proximais/patologia , Camundongos Endogâmicos BALB C , Transporte Proteico
10.
Int J Rheum Dis ; 22(12): 2143-2150, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31631507

RESUMO

AIM: The characteristics and the pathogenesis of the concomitant antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and immunoglobulin G4-related disease (IgG4-RD) have not been elucidated. METHOD: We included 92 AAV patients with renal biopsy results. Among them, 10 patients met both AAV and IgG4-RD criteria (concomitant group). The IgG subclasses of myeloperoxidase (MPO)-ANCA in both serum and renal tissue were measured and complement activation components were detected in serum. RESULTS: Patients in the concomitant group had both elevated serum IgG4 levels and positive MPO-ANCA. They had higher levels of eosinophil counts, serum globulin, IgG, IgE and C-reactive protein than patients in the AAV alone group. All 10 patients had glomerulonephritis with crescents and seven patients also had segmental necrosis of the glomerular capillary wall. Most of them also presented with storiform fibrosis and lymphoplasmacytic infiltration in renal interstitium with IgG4 positive plasma cells more than 10/high-power field. Eight patients achieved remission with improved renal function, the other two patients were on maintenance dialysis. The IgG4 subclass of MPO-ANCA was higher in the concomitant group than that in AAV alone group. A merge of IgG4 and MPO immunofluorescence was observed in parts of the mesangium of concomitant AAV and IgG4-RD patients. For complement components, Bb and mannose-binding lectin were elevated in serum of concomitant AAV and IgG4-RD patients. CONCLUSION: We showed a new overlap syndrome of AAV and IgG4-RD, in which the IgG4 subclass of ANCA may be a pathogenic factor.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Anticorpos Anticitoplasma de Neutrófilos/sangue , Doença Relacionada a Imunoglobulina G4/diagnóstico , Imunoglobulina G/sangue , Nefropatias/diagnóstico , Rim/imunologia , Peroxidase/imunologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Ativação do Complemento , Proteínas do Sistema Complemento/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Doença Relacionada a Imunoglobulina G4/sangue , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Rim/patologia , Nefropatias/sangue , Nefropatias/imunologia , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Neth J Med ; 77(7): 243-254, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31582582

RESUMO

Monoclonal gammopathy of renal significance (MGRS) includes all kidney disorders caused by a monoclonal protein (M-protein) secreted by a small plasma cell clone or other B-cell clones in patients who do not meet the diagnostic criteria for multiple myeloma or other B-cell malignancies. The underlying disorder in patients with MGRS is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). MGRS-associated kidney disorders are various and the list is still expanding. The kidney disorders can manifest as glomerular diseases, tubulopathies, and vascular involvement with varying clinical presentations. Diagnosis is often challenging because of the wide spectrum of MGRS, and it is difficult to establish a pathogenic link between the presence of the M-protein or serum free light chains and kidney diseases; further complicating accurate diagnosis is the high incidence of MGUS and/or kidney disorders, independent of MGRS, in elderly patients. However, MGRS can significantly impair kidney function. Because treatment can stop and also reverse kidney disease, early recognition is of great importance. A combined haematologic and nephrologic approach is crucial to establish the causative role of the M-protein in the pathogenesis of kidney disease. Clone-directed therapy, which may include autologous stem cell transplantation in eligible patients, often results in improved outcomes. In this review, we discuss the histopathologic classification of MGRS lesions, provide a renal and haematologic diagnostic workup, discuss treatment options for MGRS, and introduce a Benelux MGRS Working Group.


Assuntos
Nefropatias , Gamopatia Monoclonal de Significância Indeterminada , Transplante de Células-Tronco/métodos , Transplante Autólogo/métodos , Biópsia/métodos , Gerenciamento Clínico , Humanos , Nefropatias/imunologia , Nefropatias/patologia , Nefropatias/terapia , Gamopatia Monoclonal de Significância Indeterminada/sangue , Gamopatia Monoclonal de Significância Indeterminada/patologia , Gamopatia Monoclonal de Significância Indeterminada/terapia
12.
Food Funct ; 10(9): 5981-5999, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31478545

RESUMO

The kidneys and brain share similarities in anatomy and vaso-regulation and exhibit clinical interactions in various diseases. To investigate the probable mechanism of kidney to brain crosstalk, we developed an in vivo model of renal injury in mice through intoxication with the oxidative stress inducer, tBHP. Proteinuria, abnormalities in the renal tubules and KIM1 activation were found in tBHP intoxicated animals. Due to this renal pathophysiology, various pro-inflammatory molecules (TNF-α, IL-1ß, IL-6, ICAM-1, VCAM-1) especially TNF-α, entered into the brain from kidneys, triggering cerebral inflammatory cascades leading to behavioral anomalies in association with membrane lipid peroxidation, BBB disruption and brain morphological alterations. Moreover, increased levels of reactive oxygen species, decreased antioxidant enzyme activity and an altered GSH/GSSG ratio were found in both these organs. Here, we introduced mangiferin as a protective molecule because of its anti-inflammatory and antioxidant properties. Mangiferin via inhibition of apoptosis and activation of the PI3K/Akt pathway protected the kidneys. It restored the deleterious phenomena in the damaged brain by downregulating the JNK and p38MAPK mediated pro-apoptotic cascade and activating the intracellular antioxidant thioredoxin, thereby protecting against tBHP induced nephropathy mediated neuropathophysiology.


Assuntos
Encéfalo/efeitos dos fármacos , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Xantonas/administração & dosagem , terc-Butil Hidroperóxido/toxicidade , Animais , Apoptose/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Rim/citologia , Rim/imunologia , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Nefropatias/fisiopatologia , Masculino , Camundongos , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/imunologia , Espécies Reativas de Oxigênio , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Semin Nephrol ; 39(5): 496-504, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31514913

RESUMO

The extent of the systemic inflammatory response following infectious or noninfectious insults is related to impaired patient outcome. Pregnancy is associated with immunotolerance and an increased glomerular filtration rate. EA-230 is a newly developed synthetic linear tetrapeptide derived from the "pregnancy hormone" human chorionic gonadotropin. In this review, we describe the immunomodulatory and renoprotective properties of EA-230 in preclinical animal models, phase 1 studies in humans and phase 2a studies performed during human experimental endotoxemia. In addition, details pertaining to the design of a recently completed phase 2b study in 180 patients who underwent cardiac surgery to investigate the safety and immunomodulatory and renoprotective properties of EA-230 are discussed.


Assuntos
Imunidade/efeitos dos fármacos , Nefropatias/imunologia , Nefropatias/prevenção & controle , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Animais , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos
14.
J Vet Intern Med ; 33(5): 2096-2104, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31444996

RESUMO

BACKGROUND: Rapidly progressive glomerulonephritis has been described in dogs that seroreact to Borrelia burgdorferi, but no studies have compared clinicopathologic differences in Lyme-seroreactive dogs with protein-losing nephropathy (PLN) versus dogs with Borrelia-seronegative PLN. HYPOTHESIS/OBJECTIVES: Dogs with Borrelia C6 antigen-seroreactive PLN have distinct clinicopathologic findings when compared to dogs with Borrelia seronegative PLN. ANIMALS: Forty dogs with PLN and Borrelia C6 antigen seroreactivity and 78 C6-seronegative temporally matched dogs with PLN. METHODS: Retrospective prevalence case-control study. Clinical information was retrieved from records of dogs examined at the University of California, Davis, Veterinary Medical Teaching Hospital. Histopathologic findings in renal tissue procured by biopsy or necropsy of dogs with PLN were reviewed. RESULTS: Retrievers and retriever mixes were overrepresented in seroreactive dogs (P < .001). Seroreactive dogs were more likely to have thrombocytopenia (P < .001), azotemia (P = .002), hyperphosphatemia (P < .001), anemia (P < .001), and neutrophilia (P = .003). Hematuria, glucosuria, and pyuria despite negative urine culture were more likely in seroreactive dogs (all P ≤ .002). Histopathologic findings were consistent with immune-complex glomerulonephritis in 16 of 16 case dogs and 7 of 23 control dogs (P = 006). Prevalence of polyarthritis was not different between groups (P = .17). CONCLUSIONS AND CLINICAL IMPORTANCE: C6 seroreactivity in dogs with PLN is associated with a clinicopathologically distinct syndrome when compared with other types of PLN. Early recognition of this syndrome has the potential to improve outcomes through specific aggressive and early treatment.


Assuntos
Borrelia/imunologia , Doenças do Cão/microbiologia , Nefropatias/veterinária , Doença de Lyme/veterinária , Animais , Antígenos de Bactérias/sangue , Artrite/epidemiologia , Artrite/veterinária , Estudos de Casos e Controles , Doenças do Cão/imunologia , Cães , Nefropatias/imunologia , Nefropatias/microbiologia , Nefropatias/patologia , Doença de Lyme/imunologia , Doença de Lyme/patologia , Estudos Retrospectivos
15.
Rheumatol Int ; 39(11): 2005-2014, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31401698

RESUMO

Idiopathic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of diseases that are often difficult to diagnose due to the wide range of clinical manifestations. Notably, renal involvement is a serious organ complication, which usually requires intensive immunosuppressive therapy and is prone to recurrence. In recent years, there has been some progress regarding the understanding of the pathogenesis of the diseases. It has been shown that both cocaine and levamisole, which is a common adulterant of cocaine, can trigger the formation of ANCAs and lead to the corresponding symptoms. We report two cases of AAV with different renal manifestations associated with cocaine consumption. Furthermore, we performed a review of the literature to identify, characterize and describe histologically documented cases of renal involvement in AAV, related to cocaine abuse. Cocaine/levamisole-induced vasculitis may, therefore, mimic idiopathic AAV. Although the detection of ANCA and anti-PR3 (proteinase 3, PR3) as well as anti-MPO antibodies (myeloperoxidase, MPO) are the serological hallmark of idiopathic AAV, certain clinical- and antibody constellations should lead to consideration of illicit drugs as inductors of the disease. Especially in young patients, certain serologic constellations (e.g., PR3 and MPO double positivity, positive antinuclear antibodies, low complement level, and positive testing for antiphospholipid antibodies), skin involvement, musculoskeletal symptoms and hematologic (anemia, leukopenia) affections should prompt testing for cocaine and levamisole consumption via urine drug testing. Treatment includes both immunosuppressive approaches and drug cessation but is difficult since many patients continue cocaine consumption.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/induzido quimicamente , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Cocaína/efeitos adversos , Nefropatias/induzido quimicamente , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Humanos , Nefropatias/imunologia , Masculino , Adulto Jovem
16.
Adv Exp Med Biol ; 1165: 423-441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399977

RESUMO

Chronic kidney disease (CKD) is a public health problem worldwide, with increasing incidence and prevalence. The mechanisms underlying the progression to end-stage renal disease (ESRD) is not fully understood. The complement system was traditionally regarded as an important part of innate immunity required for host protection against infection and for maintaining host hemostasis. However, compelling evidence from both clinical and experimental studies has strongly incriminated complement activation as a pivotal pathogenic mediator of the development of multiple renal diseases and progressive replacement of functioning nephrons by fibrosis. Both anaphylatoxins, i.e., C3a and C5a, and membrane attack complex (MAC) contribute to the damage that occurs during chronic renal progression through various mechanisms including direct proinflammatory and fibrogenic activity, chemotactic effect, activation of the renal renin-angiotensin system, and enhancement of T-cell immunity. Evolving understanding of the mechanisms of complement-mediated renal injury has led to the emergence of complement-targeting therapeutics. A variety of specific antibodies and inhibitors targeting complement components have shown efficacy in reducing disease in animal models. Moreover, building on these advances, targeting complement has gained encouraging success in treating patients with renal diseases such as atypical hemolytic uremic syndrome (aHUS). Nevertheless, it still requires a great deal of effort to develop inhibitors that can be applied to treat more patients effectively in routine clinical practice.


Assuntos
Ativação do Complemento , Nefropatias/imunologia , Animais , Síndrome Hemolítico-Urêmica Atípica , Proteínas do Sistema Complemento , Fibrose , Humanos , Rim/patologia
17.
Food Funct ; 10(8): 5018-5031, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31355385

RESUMO

Maternal restriction of dietary proteins during pregnancy and lactation is known to induce renal disease in later life. High fructose intake causes metabolic syndrome, which results in an increased risk of chronic kidney disease development. We investigated whether quercetin intake during lactation affects high-fructose-diet-induced inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring exposed to maternal normal-protein (NP) or low-protein (LP) diets. Pregnant Wistar rats received diets containing 20% (NP) or 8% (LP) casein, and 0 or 0.2% quercetin containing NP diets (NP/NP or NP/NPQ) in experiment (Expt.) 1 and 0 or 0.2% quercetin containing LP diets (LP/LP or LP/LPQ) in Expt. 2 during lactation. At weaning, pups that received a diet of distilled water (Wa) or 10% fructose solution (Fr) were divided into six groups: NP/NP/Wa, NP/NP/Fr, NP/NPQ/Fr in Expt. 1, and LP/LP/Wa, LP/LP/Fr, LP/LPQ/Fr in Expt. 2. At week 12, macrophage infiltration, mRNA levels of TNF-α and IL-6, and markers of autophagy flux in the kidneys of male offspring were examined. We found that macrophage number and, TNF-α and IL-6 mRNA levels increased in the kidneys of the NP/NP/Fr or LP/LP/Fr, respectively. Conversely, macrophage number and IL-6 levels in the NP/NPQ/Fr or LP/LPQ/Fr decreased. LC3B-II levels were downregulated in the NP/NP/Fr or LP/LP/Fr rats. In contrast, LC3B-II levels were upregulated, while p62 levels were downregulated in the NP/NPQ/Fr and LP/LPQ/Fr rats. In conclusion, maternal quercetin intake during lactation may cause long-term alterations in inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring.


Assuntos
Autofagia/efeitos dos fármacos , Frutose/efeitos adversos , Nefropatias/prevenção & controle , Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Quercetina/administração & dosagem , Animais , Feminino , Frutose/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/imunologia , Nefropatias/fisiopatologia , Lactação , Masculino , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
18.
Monoclon Antib Immunodiagn Immunother ; 38(4): 137-144, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31361582

RESUMO

Among multiple parameters, applied in the immunologic monitoring of transplantation, the levels of serum soluble CD30 (sCD30) and peripheral regulatory T cells (Tregs) are very promising. These are relatively new biomarkers, considered to reflect immune activation and tolerance in solid organ transplantation. Results are shown here from a preliminary study on the relevance of sCD30 and Tregs in the monitoring of the early post-transplantation period. Sixteen patients with chronic liver or kidney disease were examined. Nine of them were further selected for transplantation. Follow-up of sCD30 and Tregs was carried out during the first month after transplantation. Until day 30 (D30) after transplantation, a progressive decrease in sCD30 levels was observed in all patients. Conversely, the dynamic of Tregs was dependent on the transplanted organ: in liver recipients, an increase of Tregs was detected at day 7 (D7) followed by a gradual decrease until D30, whereas in kidney recipients, a sustained downward trend starting on D7 was observed. In liver recipients, the increase in Tregs preceded albumin normalization, whereas in kidney recipients, sCD30 was found to have predictive significance for the creatinine levels. Our results demonstrated that peripheral blood sCD30 and Tregs are valuable parameters in the immunologic monitoring of transplanted patients.


Assuntos
Sobrevivência de Enxerto/imunologia , Antígeno Ki-1/metabolismo , Nefropatias/imunologia , Transplante de Rim/métodos , Hepatopatias/imunologia , Transplante de Fígado/métodos , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Biomarcadores/análise , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Nefropatias/metabolismo , Nefropatias/cirurgia , Hepatopatias/metabolismo , Hepatopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Complicações Pós-Operatórias , Prognóstico , Adulto Jovem
19.
Am J Kidney Dis ; 74(4): 529-537, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31303350

RESUMO

Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non-small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/imunologia , Imunoterapia/efeitos adversos , Nefropatias/induzido quimicamente , Nefropatias/imunologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Imunoterapia/tendências , Nefropatias/diagnóstico , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Masculino
20.
J Immunol Res ; 2019: 2121849, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31317046

RESUMO

Background: Mesangial cells play a prominent role in the development of inflammatory diseases and autoimmune disorders of the kidney. Mesangial cells perform the essential functions of helping to ensure that the glomerular structure is stable and regulating capillary flow, and activated mesangial cells acquire proinflammatory activities. We investigated whether activated mesangial cells display immune properties and control the development of T cell immunity. Methods: Flow cytometry analysis was used to study the expression of antigen-presenting cell surface markers and costimulatory molecules in mesangial cells. CD4+ T cell activation induced by mesangial cells was detected in terms of T cell proliferation and cytokine production. Results: IFN-γ-treated mesangial cells express membrane proteins involved in antigen presentation and T cell activation, including MHC-II, ICAM-1, CD40, and CD80. This finding suggests that activated mesangial cells can take up and present antigenic peptides to initiate CD4+ T cell responses and thus act as nonprofessional antigen-presenting cells. Polarization of naïve CD4+ T cells (Th0 cells) towards the Th1 phenotype was induced by coculture with activated mesangial cells, and the resulting Th1 cells showed increased mRNA and protein expression of inflammation-associated genes. Conclusion: Mesangial cells can present antigen and modulate CD4+ T lymphocyte proliferation and differentiation. Interactions between mesangial cells and T cells are essential for sustaining the inflammatory response in a variety of glomerulonephritides. Therefore, mesangial cells might participate in immune function in the kidney.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Células Mesangiais/imunologia , Animais , Apresentação do Antígeno/efeitos dos fármacos , Células Apresentadoras de Antígenos/efeitos dos fármacos , Células Apresentadoras de Antígenos/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Interferon gama/metabolismo , Nefropatias/imunologia , Ativação Linfocitária/imunologia , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Th1/imunologia , Células Th1/metabolismo
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