RESUMO
Although kidney transplantation is the best treatment for end stage kidney disease, the benefits are limited by factors such as the short fall in donor numbers, the burden of immunosuppression and graft failure. Although there have been improvements in one-year outcomes, the annual rate of graft loss beyond the first year has not significantly improved, despite better therapies to control the alloimmune response. There is therefore a need to develop alternative strategies to limit kidney injury at all stages along the transplant pathway and so improve graft survival. Complement is primarily part of the innate immune system, but is also known to enhance the adaptive immune response. There is increasing evidence that complement activation occurs at many stages during transplantation and can have deleterious effects on graft outcome. Complement activation begins in the donor and occurs again on reperfusion following a period of ischemia. Complement can contribute to the development of the alloimmune response and may directly contribute to graft injury during acute and chronic allograft rejection. The complexity of the relationship between complement activation and allograft outcome is further increased by the capacity of the allograft to synthesise complement proteins, the contribution complement makes to interstitial fibrosis and complement's role in the development of recurrent disease. The better we understand the role played by complement in kidney transplant pathology the better placed we will be to intervene. This is particularly relevant with the rapid development of complement therapeutics which can now target different the different pathways of the complement system. Combining our basic understanding of complement biology with preclinical and observational data will allow the development and delivery of clinical trials which have best chance to identify any benefit of complement inhibition.
Assuntos
Transplante de Rim , Rejeição de Enxerto , Ativação do Complemento , Rim , Proteínas do Sistema Complemento/metabolismo , Sobrevivência de EnxertoRESUMO
INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.
Assuntos
Injúria Renal Aguda , Anticorpos Monoclonais Humanizados , Função Retardada do Enxerto , Interleucina-18/sangue , Transplante de Rim , Doadores de Tecidos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
BACKGROUND: Ex vivo perfusion is used in our unit for kidneys donated after cardiac death (DCD). Perfusion flow index (PFI), resistance, and perfusate glutathione S-transferase (GST) can be measured to assess graft viability. We assessed whether measurements taken during perfusion could predict long-term outcome after transplantation. METHODS: All DCD kidney transplants performed from 2002 to 2014 were included in this study. The exclusion criteria were: incomplete data, kidneys not machine perfused, kidneys perfused in continuous mode, and dual transplantation. There were 155 kidney transplantations included in the final analysis. Demographic data, ischemia times, donor hypertension, graft function, survival and machine perfusion parameters after 3 hours were analyzed. Each perfusion parameter was divided into 3 groups as high, medium, and low. Estimated glomerular filtration rate was calculated at 12 months and then yearly after transplantation. RESULTS: There was a significant association between graft survival and PFI and GST (P values, .020 and .022, respectively). PFI was the only independent parameter to predict graft survival. CONCLUSIONS: A low PFI during ex vivo hypothermic perfusion is associated with inferior graft survival after DCD kidney transplantation. We propose that PFI is a measure of the health of the graft vasculature and that a low PFI indicates vascular disease and therefore predicts a worse long-term outcome.
Assuntos
Glutationa Transferase/análise , Sobrevivência de Enxerto , Transplante de Rim , Perfusão/métodos , Adulto , Morte , Feminino , Humanos , Hipertensão , Rim , Masculino , Pessoa de Meia-Idade , Doadores de TecidosRESUMO
BACKGROUND: In 2013 NHS England commissioned the use of eculizumab for both new patients with atypical haemolytic uraemic syndrome (aHUS) and those undergoing transplantation. This national service is delivered locally but coordinated by an expert centre at the Newcastle upon Tyne Hospitals NHS Foundation Trust. RESULTS: In the first year of service, 43 aHUS patients received eculizumab, 15 children and 28 adults. Twenty-three were new patients and 20 prevalent. Fifteen of the 23 new patients required dialysis before eculizumab was started, 8 of these recovered renal function. Twelve of the 20 prevalent patients who received eculizumab were transplant patients, 8 with prophylactic use and 4 for recurrent disease; the outcome in all was good. Eculizumab was withdrawn in 14 patients, 5 were patients who had not recovered renal function. In 3 of the 14 patients, it was necessary to reintroduce eculizumab because of recurrent disease (2 extra-renal and 1 renal). There were 2 deaths in the 43 patients, and neither was associated with use of eculizumab. There were no episodes of meningococcal disease. CONCLUSIONS: The establishment of this national service has enabled aHUS patients in England to receive eculizumab when they need it for as long as they need it.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Rim/fisiopatologia , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Criança , Pré-Escolar , Inglaterra , Feminino , Humanos , Masculino , Infecções Meningocócicas/prevenção & controle , Pessoa de Meia-Idade , Diálise Renal/métodos , Adulto JovemRESUMO
Atypical hemolytic uremic syndrome is a rare disease associated with genetic or acquired defects in complement regulation which frequently leads to renal failure. Disease often recurs early after kidney transplantation, leading to a rapid irreversible loss of function. Extrarenal features, such as hemolysis and thrombocytopenia, may not always occur, and diagnosis is made by demonstrating the classic features of thrombotic microangiopathy on renal biopsy. Eculizumab, a terminal complement inhibitor, has been used successfully to treat fulminant early recurrent disease after transplantation. We describe a case of disease recurrence presenting in the second year after transplantation with a gradual decline in function and the first report of eculizumab treatment for chronic thrombotic microangiopathy in a transplanted kidney. The resultant diagnostic challenges and successful response to eculizumab in this setting are discussed.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Transplante de Rim , Disfunção Primária do Enxerto/etiologia , Microangiopatias Trombóticas/tratamento farmacológico , Doença Crônica , Feminino , Humanos , Rim/patologia , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/diagnóstico , Disfunção Primária do Enxerto/tratamento farmacológico , Recidiva , Microangiopatias Trombóticas/etiologiaRESUMO
Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).
Assuntos
Diabetes Mellitus Tipo 1/cirurgia , Rejeição de Enxerto/epidemiologia , Antígenos HLA/imunologia , Transplante das Ilhotas Pancreáticas/efeitos adversos , Isoanticorpos/sangue , Doadores de Tecidos , Adulto , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Teste de Histocompatibilidade , Humanos , Incidência , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/antagonistas & inibidores , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Microangiopatias Trombóticas/prevenção & controle , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Anticorpos Monoclonais Humanizados/farmacocinética , Terapia Combinada , Feminino , Síndrome Hemolítico-Urêmica/sangue , Síndrome Hemolítico-Urêmica/genética , Síndrome Hemolítico-Urêmica/terapia , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Troca Plasmática , Contagem de Plaquetas , Qualidade de Vida , Adulto JovemAssuntos
Abdome Agudo/etiologia , Dor Abdominal/etiologia , Edema/etiologia , Rim/patologia , Síndrome Nefrótica/complicações , Síndrome Nefrótica/diagnóstico , Anti-Inflamatórios/uso terapêutico , Edema/diagnóstico , Humanos , Hipoalbuminemia/metabolismo , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/patologia , Prednisolona/uso terapêutico , Proteinúria/metabolismoRESUMO
We report here a young female who underwent a successful deceased donor liver transplant for hepatic vein thrombosis. Five years after transplantation she developed postpartum atypical hemolytic uremic syndrome (aHUS). She did not recover renal function. Mutation screening of complement genes in her DNA did not show any abnormality. Mutation screening of DNA available from the donor showed a nonsense CFH mutation leading to factor H deficiency. Genotyping of the patient showed that she was homozygous for an aHUS CD46 at-risk haplotype. In this individual, the development of aHUS has been facilitated by the combination of a trigger (pregnancy), an acquired rare genetic variant (CFH mutation) and a common susceptibility factor (CD46 haplotype).
Assuntos
Fator H do Complemento/genética , Transplante de Fígado , Período Pós-Parto , Adulto , Síndrome de Budd-Chiari/cirurgia , Feminino , Homozigoto , HumanosRESUMO
The evolution of man has been characterised by recurrent episodes of migration and settlement with infectious disease a constant threat. This long history of demographic change, together with the action of evolutionary forces such as natural selection and genetic drift, has shaped human genetic diversity. In particular, the interaction between humans, pathogens and the environment has played a crucial role in generating patterns of human genetic variation. The complement system plays a crucial role in the early protective immune response after exposure to a pathogen. Pathogens, over time, have developed mechanisms to circumvent the effects of complement which in turn has led to development of a more complex complement system. During the evolution of the complement system genes coding complement proteins have evolved polymorphisms, some of which have a functional effect, and this may reflect human-pathogen interaction and geographical origin. An example is the polymorphism Ile62Val (rs800292 (A>G)) in the complement regulator Factor H gene which alters the susceptibility to age-related macular degeneration (AMD), with the Ile62 polymorphism protecting against AMD. When sub-Saharan African and European populations are compared, the frequency of this polymorphism shows a very marked geographical distribution. Polymorphisms in other complement genes such as complement factor B show similar trends. This paper describes the geographical variation present in complement genes and discusses the implications of these observations. The analysis of genetic variation in complement genes is a promising tool to unravel mechanisms of host-pathogen interaction and can provide new insights into the evolution of the human immune system.
Assuntos
Proteínas do Sistema Complemento/genética , Variação Genética , Degeneração Macular/genética , África Subsaariana , Proteínas do Sistema Complemento/metabolismo , Europa (Continente) , Evolução Molecular , Predisposição Genética para Doença , Genótipo , Geografia , Humanos , Degeneração Macular/imunologia , Polimorfismo de Nucleotídeo Único , Seleção GenéticaRESUMO
Experimental unilateral ureteral obstruction (UUO) is widely used to study renal fibrosis; however, renal injury can only be scored semiobjectively by histology. We sought to improve the UUO model by reimplanting the obstructed ureter followed by removal of the contralateral kidney, thus allowing longitudinal measurements of renal function. Mice underwent UUO for different lengths of time before ureteral reimplantation and contralateral nephrectomy. Measurement of blood urea nitrogen (BUN) allows objective evaluation of residual renal function. Seven weeks after reimplantation and contralateral nephrectomy, mean BUN levels were increased with longer duration of UUO. Interstitial expansion, fibrosis, and T-cell and macrophage infiltration were similar in kidneys harvested after 10 days of UUO or following 10 weeks of ureter reimplantation, suggesting that the inflammatory process persisted despite relief of obstruction. Urinary protein excretion after reimplantation was significantly increased compared to control animals. Our study shows that functional assessment of the formerly obstructed kidney can be made after reimplantation and may provide a useful model to test therapeutic strategies for reversing renal fibrosis and preserving or restoring renal function.
Assuntos
Modelos Animais de Doenças , Rim/fisiopatologia , Ureter/cirurgia , Obstrução Ureteral/cirurgia , Animais , Feminino , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , NefrectomiaRESUMO
Renal tubular epithelial cells (TECs) respond diffusely to local infection, with the release of multiple cytokines, chemokines and other factors that are thought to orchestrate the cellular constituents of the innate immune response. We have investigated whether the Toll-like receptors TLR4 and TLR2, which are present on tubular epithelium and potentially detect a range of bacterial components, co-ordinate this inflammatory response acting through nuclear factor-kappa B (NF-kappaB). Primary cultures of TECs were grown from C57BL/6, C3H/HeN, C3H/HeJ, TLR2 and TLR4 knock-out mice. Cell monolayers were stimulated with lipopolysaccharide (LPS) and synthetic TLR2 and 4 agonists. The innate immune response was quantified by measurement of the cytokines tumour necrosis factor (TNF)-alpha and KC (IL-8 homologue) in cell supernatants by enzyme-linked immunosorbent assay. Cultured TECs grown from healthy mice produced the cytokines TNF-alpha and KC in response to stimulation by LPS and synthetic TLR2 and TLR4 agonists. Cells lacking the respective TLRs had a reduced response to stimulation. The TLR2- and TLR4-mediated response to stimulation was dependent on NF-kappaB signalling, as shown by curcumin pretreatment of TECs. Finally, apical stimulation of these TLRs elicited basal surface secretion of TNF-alpha and KC (as well as the reverse), consistent with the biological response in vivo. Our data highlight the potential importance of TLR-dependent mechanisms co-ordinating the innate immune response to upper urinary tract infection.
Assuntos
Infecções Bacterianas/imunologia , Túbulos Renais/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Polaridade Celular , Células Cultivadas , Citocinas/imunologia , Células Epiteliais/imunologia , Expressão Gênica , Receptores de Lipopolissacarídeos/genética , Lipopolissacarídeos , Antígeno 96 de Linfócito/genética , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genéticaRESUMO
This review discusses recent advances in the understanding of how the common pathogen, uropathogenic Escherichia coli, interacts with the host to lead to infection.
Assuntos
Infecções por Escherichia coli/microbiologia , Fímbrias Bacterianas , Infecções Urinárias/microbiologia , Escherichia coli/imunologia , Escherichia coli/patogenicidade , Infecções por Escherichia coli/imunologia , Feminino , Humanos , Imunidade Inata , Infecções Urinárias/imunologia , VirulênciaRESUMO
Evidence suggesting a direct role for proteinuria in the pathogenesis of renal tubulointerstitial fibrosis is accumulating. However the mechanism by which proteinuria leads to injury is unknown. In proteinuric states complement proteins are filtered through the glomerulus and could contribute to the tubular damage. The aim of this study was to investigate the role of complement activation in the progression of interstitial fibrosis. To determine whether complement activation may be responsible for the pro-fibrotic response that occurs in the tubulointerstitial compartment we stimulated primary cultures of proximal tubular epithelial cells with membrane attack complex, C5b-9. This led to increased mRNA concentrations of both collagen type IV and its intracellular chaperone, Heat Shock Protein 47 (HSP47). To determine whether this occurred in vivo Adriamycin was used to induce proteinuria in female Balb/c mice. The expression of collagen type IV and HSP47 was increased in proteinuric mice compared to control mice. In proteinuric mouse kidney, C3 was deposited at sites of tubulointerstitial injury and there was a relationship between C3 deposition and immunochemical staining for collagen type IV and HSP47. In situ hybridization suggested that the renal tubular epithelium was actively expressing HSP47 mRNA and, by implication, excess collagen. These observations support the hypothesis that complement activation on tubular epithelial cells can directly increase the pro-fibrotic process associated with tubulointerstitial damage.
Assuntos
Colágeno/biossíntese , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Túbulos Renais/metabolismo , Nefrite Intersticial/imunologia , Albuminúria/imunologia , Albuminúria/metabolismo , Animais , Células Cultivadas , Doxorrubicina , Células Epiteliais/metabolismo , Feminino , Proteínas de Choque Térmico HSP47 , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Camundongos , Camundongos Endogâmicos BALB C , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Complement deficiency predisposes to autoimmune renal disease. Since complement deficient mice are increasingly used to study the immunopathogenesis of renal disease we have determined whether mice deficient in C3 or C4 are susceptible to spontaneous immune-mediated renal injury. METHODS: C3-deficient, C4-deficient and complement-sufficient, wild-type mice were maintained in standard conditions for 1 year at which stage renal function, renal histology, circulating antibody and autoantibody levels were assessed. RESULTS: No significant decline in renal function was demonstrated in the complement-deficient mice. However, there was histological evidence of glomerular injury in both the C3- and C4-deficient mice, but of insufficient severity to alter function. Serum IgG2a concentration was significantly lower in C3- and C4-deficient mice. In contrast C3-deficient mice had higher concentrations of serum IgG2b. There was a tendency for mice from all groups, including the complement-sufficient mice, to develop autoantibodies. C4-deficient mice had higher titres of anti-dsDNA IgG but otherwise deficient mice had similar autoantibody titres to controls. CONCLUSION: We conclude that C4-deficient mice demonstrate a small increase in autoantibody production at 1 year of age compared to C3-deficient and wild-type mice. Furthermore, although complement-deficient mice exhibit glomerular changes, they are of minor functional significance, and are unlikely to affect the study of experimentally induced renal disease in these mice.
Assuntos
Doenças Autoimunes/fisiopatologia , Complemento C3/deficiência , Complemento C4/deficiência , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Animais , Autoanticorpos/biossíntese , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Feminino , Secções Congeladas/métodos , Glomerulonefrite/sangue , Glomerulonefrite/patologia , Glomerulonefrite/fisiopatologia , Imunoglobulina G/biossíntese , Imunoglobulina G/sangue , Imunoglobulina M/biossíntese , Imunoglobulina M/sangue , Imuno-Histoquímica/métodos , Glomérulos Renais/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos MutantesAssuntos
Proteínas do Sistema Complemento/urina , Túbulos Renais/fisiopatologia , Nefrite Intersticial/fisiopatologia , Proteinúria/fisiopatologia , Animais , Antígenos CD , Permeabilidade Capilar , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento/urina , Proteínas do Sistema Complemento/biossíntese , Citocinas/biossíntese , Progressão da Doença , Fibrose , Mesângio Glomerular/fisiopatologia , Humanos , Túbulos Renais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Camundongos , Modelos Biológicos , Receptor da Anafilatoxina C5a , Receptores de Complemento/deficiênciaAssuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Rejeição de Enxerto/etiologia , Transplante de Rim , Policondrite Recidivante/complicações , Vasculite/complicações , Vasculite/imunologia , Idoso , Feminino , Humanos , Complicações Pós-Operatórias , Recidiva , Fatores de Tempo , Transplante HomólogoRESUMO
To assess the role of complement in renal infection, we studied a model of Escherichia coli-induced pyelonephritis in mice deficient in complement components C3 and C4. Renal infection occurred less frequently in C3- and C4-deficient mice compared with wild-type mice. In vitro, renal epithelial cells internalized fewer bacteria in the absence of C3 or in the presence of blockade of C3 bound to the bacteria. Moreover, upregulation of epithelial C3 production by stimulation with lipopolysaccharide enhanced bacterial internalization. Here we provide evidence that uropathogenic E. coli might use host C3 to invade the renal epithelium and that local complement production is sufficient for the bacteria to achieve this effect.
Assuntos
Complemento C3/fisiologia , Escherichia coli/crescimento & desenvolvimento , Rim/microbiologia , Animais , Sequência de Bases , Complemento C3/biossíntese , Complemento C3/genética , Primers do DNA , Células Epiteliais/metabolismo , Infecções por Escherichia coli/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pielonefrite/fisiopatologiaRESUMO
The role of complement in autoimmune glomerulonephritis (as in other autoimmune diseases) is paradoxical, in that complement activation mediates acute inflammatory injury, yet inherited deficiency of complement may predispose to immune complex disease in particular immune complex glomerulonephritis. We have investigated the role of complement in experimentally induced glomerulonephritis in C3-deficient mice, using antibodies against the mouse glomerular basement membrane (GBM). In the acute phase of the disease, which is initiated by binding of heterologous antibody to the GBM, we confirmed that the inflammatory injury was positively complement dependent, with C3-deficient mice developing less severe injury. In contrast, in the autologous phase of the disease, mediated by the immune response against the heterologous antibody fixed in the GBM, the disease was negatively complement dependent. That is, by 14 days after disease induction the C3-deficient mice had heavier proteinuria and more severe uremia (p < 0.001) compared to the complement sufficient mice. The C3-deficient mice also showed a greater accumulation of electron-dense deposits in the GBM. These findings were reproduced in an accelerated model of this disease in which C3-deficient mice also develop more severe functional disturbance and demonstrate a higher rate of immune complex deposition. These data illustrate the potential for the net effect of complement to switch from a detrimental to a protective mode at different stages of autoimmune injury.