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1.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445337

RESUMO

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFß2 and IL1ß. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.


Assuntos
Transdiferenciação Celular/genética , Rim/patologia , MicroRNAs/fisiologia , Miocárdio/patologia , Animais , Células Cultivadas , Células Endoteliais/patologia , Células Endoteliais/fisiologia , Fibrose/genética , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Rim/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patologia
2.
Transpl Int ; 34(1): 49-58, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131097

RESUMO

There has been increasing use of organs from extended criteria or donation after circulatory death donors to meet the demands of the transplant waiting list. Over the past decade, there has been considerable progress in technologies to preserve organs prior to transplantation to improve the function of these marginal organs. This has led to the development of normothermic machine perfusion, whereby an organ is perfused with warmed, oxygenated blood and nutrients to resume normal physiological function in an isolated ex-vivo platform. With this advance in preservation comes significant opportunities to recondition, repair and regenerate organs prior to transplantation using cellular therapies. This review aims to discuss the possibilities of machine perfusion technology; highlighting the potential for organ-directed reconditioning and the future avenues for investigation in this field.


Assuntos
Transplante de Fígado , Preservação de Órgãos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Perfusão , Doadores de Tecidos
3.
Am J Transplant ; 21(4): 1402-1414, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32506663

RESUMO

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC® ) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC-treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast-enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)-1ß (P = .050), and upregulation of IL-10 (P < .047) and Indolamine-2, 3-dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC-treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.


Assuntos
Transplante de Rim , Traumatismo por Reperfusão , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Rim , Transplante de Rim/efeitos adversos , Preservação de Órgãos , Perfusão , Traumatismo por Reperfusão/prevenção & controle
5.
Nat Metab ; 2(11): 1350-1367, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33168981

RESUMO

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-ß1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.


Assuntos
Epitélio/patologia , Cirrose Hepática/genética , Cirrose Hepática/patologia , Macrófagos/patologia , Proteínas Proto-Oncogênicas c-rel/genética , Animais , Polaridade Celular/genética , Marcação de Genes , Hepatócitos/patologia , Hidroxiprolina/metabolismo , Cirrose Hepática/prevenção & controle , Regeneração Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitose/genética , Comunicação Parácrina/genética , Fosfofrutoquinase-2/genética , Proteínas Proto-Oncogênicas c-rel/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-rel/metabolismo
6.
Transpl Int ; 33(12): 1650-1666, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32542834

RESUMO

Severe acute kidney injury (AKI), defined as requiring renal replacement therapy (RRT), is associated with higher mortality postheart transplantation, but its long-term renal consequences are not known. Anonymized data of 3365 patients, who underwent heart transplantation between 1995 and 2017, were retrieved from the UK Transplant Registry. Multivariable binary logistic regression was performed to identify risk factors for severe AKI requiring RRT, Kaplan-Meier analysis to compare survival and renal function deterioration of the RRT and non-RRT groups, and multivariable Cox regression model to identify predicting factors of mortality and end-stage renal disease (ESRD). 26.0% of heart recipients received RRT post-transplant. The RRT group has lower survival rates at all time points, especially in the immediate post-transplant period. However, conditional on 3 months survival, older age, diabetes and coronary heart disease, but not post-transplant RRT, were the risk factors for long-term survival. The predicting factors for ESRD were insulin-dependent diabetes, renal function at transplantation, eGFR decline in the first 3 months post-transplant, post-transplant severe AKI and transplantation era. Severe AKI requiring RRT post-transplant is associated with worse short-term survival, but has no impact on long-term mortality. It also accelerates recipients' renal function deterioration in the long term.


Assuntos
Injúria Renal Aguda , Transplante de Coração , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/terapia , Idoso , Estudos de Coortes , Humanos , Terapia de Substituição Renal , Estudos Retrospectivos , Fatores de Risco , Reino Unido/epidemiologia
7.
BMC Nephrol ; 21(1): 220, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522162

RESUMO

BACKGROUND: Post-transplant lymphoproliferative disease is a recognized complication following solid organ transplantation. This is usually a B cell disease and frequently associated with Epstein Barr virus infection, although T cell PTLD can occur. T cell PTLD is usually a monomorphic, lymphomatous disease associated with an adverse prognosis. CASE REPORT: We report a 52 year old male pre-emptive renal transplant recipient who developed severe diarrhea with weight loss following intensification of his immunosuppression due to antibody mediated rejection 3 years after transplantation. Duodenal biopsy demonstrated monoclonal CD8+ T cell duodenitis leading to increased intraepithlieal lymphocytes and sub-total villous atrophy mimicking coeliac disease. Coeliac disease was excluded by negative anti-tissue transglutaminase antibody, HLA-DQ2 and HLA-DQ8 testing. There was no evidence of lymphoma either on biopsy or CT enterography and no FDG avid disease on PET. Symptoms did not improve with reduction of immunosuppression, but resolved fully on complete withdrawal of treatment. The transplant failed and he was established on dialysis. The diagnosis was early PTLD. CONCLUSIONS: Oesophagogastroduodenoscopy with small bowel biopsies is a useful investigation for determining the cause of diarrhoea in renal transplant patients when more common causes have been excluded. This is the first report that we are aware of clonal T cell PTLD mimicking coeliac disease which only resolved after complete withdrawal of immunosuppression. As treatments for lymphoma are aggressive they are only initiated in the malignant phase and management of early stage PTLD is to minimise risk of progression by reducing immunosuppression. Any plans to retransplant will have to take into consideration the possibility that PTLD will recur.


Assuntos
Doença Celíaca/diagnóstico , Diarreia/etiologia , Duodeno/patologia , Imunossupressão/efeitos adversos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/diagnóstico , Biópsia , Diagnóstico Diferencial , Duodeno/imunologia , Endoscopia do Sistema Digestório , Humanos , Hospedeiro Imunocomprometido , Transtornos Linfoproliferativos/etiologia , Masculino , Pessoa de Meia-Idade , Linfócitos T
8.
Kidney Int ; 97(6): 1260-1274, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32386968

RESUMO

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Diacilglicerol Quinase , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Síndrome Hemolítico-Urêmica Atípica/genética , Pré-Escolar , Diacilglicerol Quinase/genética , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Reino Unido
9.
Transplantation ; 104(4): 708-714, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32224812

RESUMO

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence. The strengths of recommendations are provided in the full report. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.


Assuntos
Seleção do Doador/normas , Transplante de Rim/normas , Doadores Vivos/provisão & distribuição , Guias de Prática Clínica como Assunto/normas , Transplantados , Tomada de Decisão Clínica , Consenso , Medicina Baseada em Evidências/normas , Nível de Saúde , Humanos , Transplante de Rim/efeitos adversos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
10.
Transplantation ; 104(4S1 Suppl 1): S11-S103, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32301874

RESUMO

The 2020 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Management of Candidates for Kidney Transplantation is intended to assist health care professionals worldwide who evaluate and manage potential candidates for deceased or living donor kidney transplantation. This guideline addresses general candidacy issues such as access to transplantation, patient demographic and health status factors, and immunological and psychosocial assessment. The roles of various risk factors and comorbid conditions governing an individual's suitability for transplantation such as adherence, tobacco use, diabetes, obesity, perioperative issues, causes of kidney failure, infections, malignancy, pulmonary disease, cardiac and peripheral arterial disease, neurologic disease, gastrointestinal and liver disease, hematologic disease, and bone and mineral disorder are also addressed. This guideline provides recommendations for evaluation of individual aspects of a candidate's profile such that each risk factor and comorbidity are considered separately. The goal is to assist the clinical team to assimilate all data relevant to an individual, consider this within their local health context, and make an overall judgment on candidacy for transplantation. The guideline development process followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Guideline recommendations are primarily based on systematic reviews of relevant studies and our assessment of the quality of that evidence, and the strengths of recommendations are provided. Limitations of the evidence are discussed with differences from previous guidelines noted and suggestions for future research are also provided.


Assuntos
Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Falência Renal Crônica/cirurgia , Transplante de Rim/normas , Seleção de Pacientes , Consenso , Humanos , Falência Renal Crônica/diagnóstico , Transplante de Rim/efeitos adversos , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco
11.
Clin Med (Lond) ; 20(2): 156-160, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32188650

RESUMO

While the complement cascade is an important component of the innate immune system, uncontrolled activation can cause severe disease. This concept is illustrated by the prototypical complement-mediated renal disease atypical haemolytic uraemic syndrome (aHUS), which causes renal failure if untreated but when managed with the complement inhibitor eculizumab leaves the patient vulnerable to infection with encapsulated organisms. Complement activation is also implicated in the pathogenesis of many other renal and non-renal diseases, necessitating an understanding of complement biology and diagnostics. We review renal diseases in which complement over-activation is known to cause tissue injury; aHUS and C3 glomerulopathy. We also discuss the contribution of complement more widely to the pathophysiology of renal disease, and highlight the significance and side effects of anti-complement therapy relevant to the general physician.


Assuntos
Síndrome Hemolítico-Urêmica Atípica , Nefropatias , Ativação do Complemento , Proteínas do Sistema Complemento , Humanos , Rim
12.
Transplantation ; 104(9): 1853-1861, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150044

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are short noncoding RNAs which each cause repression of many target genes. Previous work has demonstrated that therapeutic blockade of single miRNAs is possible. miR-24-3p and miR-145-5p are reported to have a detrimental role in ischemia-reperfusion injury. As the action of miRNAs is inhibitory, we hypothesized that dual blockade of both miRNAs could synergistically upregulate shared target genes. METHODS: Quantification of miRNA expression in donated kidneys was performed using polymerase chain reaction (PCR) panels. Ischemia-reperfusion injury was modeled in vitro by placing human umbilical vein endothelial cells into a hypoxic incubator (1% O2) for 24 hours, with reoxygenation for 6 hours. RNA expression was quantified with reverse transcription quantitative polymerase chain reaction and protein expression assessed with Western blot. Antisense oligonucleotides were used to inhibit miRNAs. RESULTS: miR-24-3p and miR-145-5p were highly expressed in human kidneys following extended cold ischemia. In vitro, hypoxia caused significant upregulation of miR-24-3p (P ≤ 0.001) and miR-145-5p (P ≤ 0.001) and significant downregulation in messenger RNA of shared targets superoxide dismutase 2 (P ≤ 0.001) and heme oxygenase 1 (P ≤ 0.001). These changes were mirrored at the protein level. Dual inhibition of both miR-24-3p and miR-145-5p caused significant upregulation of superoxide dismutase 2 and heme oxygenase 1 protein following hypoxia-reoxygenation; fold change of 3.17 (P ≤ 0.05) and 6.97 (P ≤ 0.05) respectively. Dual inhibition resulted in reduced cellular reactive oxygen species production compared with negative control (P ≤ 0.05) and single blockade of miR-24-3p (P ≤ 0.01) or miR-145-5p (P ≤ 0.05). CONCLUSIONS: Dual blockade of 2 miRNAs can act synergistically to increase the expression of shared gene targets. Dual blockade of miR-24-3p and miR-145-5p represents a novel therapeutic option worthy of further research.


Assuntos
Heme Oxigenase-1/genética , Rim/metabolismo , MicroRNAs/antagonistas & inibidores , Traumatismo por Reperfusão/terapia , Superóxido Dismutase/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/análise , RNA Mensageiro/análise , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-32098865

RESUMO

OBJECTIVE: To raise awareness of complement factor I (CFI) deficiency as a potentially treatable cause of severe cerebral inflammation. METHODS: Case report with neuroradiology, neuropathology, and functional data describing the mutation with review of literature. RESULTS: We present a case of acute, fulminant, destructive cerebral edema in a previously well 11-year-old, demonstrating massive activation of complement pathways on neuropathology and compound heterozygote status for 2 pathogenic mutations in CFI which result in normal levels but completely abrogate function. CONCLUSIONS: Our case adds to a very small number of extant reports of this phenomenon associated with a spectrum of inflammatory histopathologies including hemorrhagic leukoencephalopathy and clinical presentations resembling severe acute disseminated encephalomyelitis. CFI deficiency can result in uncontrolled activation of the complement pathways in the brain resulting in devastating cerebral inflammation. The deficit is latent, but the catastrophic dysregulation of the complement system may be the result of a C3 acute phase response. Diagnoses to date have been retrospective. Diagnosis requires a high index of suspicion and clinician awareness of the limitations of first-line clinical tests of complement activity and activation. Simple measurement of circulating CFI levels, as here, may fail to diagnose functional deficiency with absent CFI activity. These diagnostic challenges may mean that the CFI deficiency is being systematically under-recognized as a cause of fulminant cerebral inflammation. Complement inhibitory therapies (such as eculizumab) offer new potential treatment, underlining the importance of prompt recognition, and real-time whole exome sequencing may play an important future role.


Assuntos
Complemento C3/deficiência , Encefalite/diagnóstico , Encefalite/etiologia , Doenças da Deficiência Hereditária de Complemento/complicações , Doenças da Deficiência Hereditária de Complemento/diagnóstico , Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Criança , Feminino , Humanos
14.
Curr Opin Pharmacol ; 49: 95-101, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31731225

RESUMO

Diseases where fibrosis plays a major role accounts for enormous morbidity and mortality and yet we have very little in our therapeutic arsenal despite decades of research and clinical trials. Our understanding of fibrosis biology is primarily built on data generated in conventional mono-culture or co-culture systems and in vivo model systems. While these approaches have undoubtedly enhanced our understanding of basic mechanisms, they have repeatedly failed to translate to clinical benefit. Recently, there had been a push to generate more physiologically relevant platforms to study fibrosis and identify new therapeutic targets. Here we review the state-of-the-art regarding the development and application of 3D complex cultures, bio-printing and precision cut slices to study pulmonary, hepatic and renal fibrosis.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Fibrose , Animais , Bioimpressão , Fibrose/tratamento farmacológico , Humanos , Esferoides Celulares , Tecidos Suporte
15.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31598213

RESUMO

The thrombotic microangiopathies (TMAs) are a group of diseases characterised by microangiopathic haemolysis, thrombocytopenia, and thrombus formation leading to tissue injury. Traditionally, TMAs have been classified as either thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS) based on the clinical presentation, with neurological involvement predominating in the former and acute kidney injury in the latter. However, as our understanding of the pathogenesis of these conditions has increased, it has become clear that this is an over-simplification; there is significant overlap in the clinical presentation of TTP and HUS, there are different forms of HUS, and TMAs can occur in other, diverse clinical scenarios. This review will discuss recent developments in the diagnosis of HUS, focusing on the different forms of HUS and how to diagnose and manage these potentially life-threatening diseases.


Assuntos
Injúria Renal Aguda , Síndrome Hemolítico-Urêmica , Púrpura Trombocitopênica Trombótica , Microangiopatias Trombóticas , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/terapia , Hemólise , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/terapia , Humanos , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/terapia
16.
Transplant Proc ; 51(6): 1785-1790, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399164

RESUMO

BACKGROUND: Hypothermic machine perfusion is used to improve renal perfusion and reduce the rate of early and late graft dysfunction. It has been used in our unit since 2001. It has 2 modes of flow: continuous or pulsatile. The aim of this study is to compare the modes of perfusion in terms of perfusion-related parameters, graft survival, and estimated glomerular filtration rate. METHODS: All donation after cardiac death kidneys between 2002 and 2014 were reviewed. A total of 64 pairs of kidneys were identified of which one kidney underwent pulsatile and the other continuous perfusion. Machine parameters including resistance and perfusion flow index levels at 0, 1, 2, 3, and 4 hours were recorded and glutathione S-transferase was measured in perfusate. Estimated glomerular filtration rate from the first week of transplant until the fifth year and graft survival rates were determined. RESULTS: Machine parameters were similar at all time points. Estimated glomerular filtration rates and graft survival were the same irrespective of perfusion mode. CONCLUSION: Pulsatile perfusion may be regarded as more physiological. However, we could not identify difference in outcome following transplant of kidneys from the same donor that had been perfused under pulsatile or continuous conditions.


Assuntos
Circulação Extracorpórea/métodos , Hipotermia Induzida/métodos , Preservação de Órgãos/métodos , Perfusão/métodos , Fluxo Pulsátil , Morte , Feminino , Taxa de Filtração Glomerular , Glutationa Transferase/análise , Sobrevivência de Enxerto , Humanos , Rim/irrigação sanguínea , Rim/fisiopatologia , Transplante de Rim , Masculino , Taxa de Sobrevida , Doadores de Tecidos , Transplantes/irrigação sanguínea , Transplantes/fisiopatologia , Resultado do Tratamento
17.
Immunology ; 157(2): 173-184, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31013364

RESUMO

Leucocyte recruitment is critical during many acute and chronic inflammatory diseases. Chemokines are key mediators of leucocyte recruitment during the inflammatory response, by signalling through specific chemokine G-protein-coupled receptors (GPCRs). In addition, chemokines interact with cell-surface glycosaminoglycans (GAGs) to generate a chemotactic gradient. The chemokine interleukin-8/CXCL8, a prototypical neutrophil chemoattractant, is characterized by a long, highly positively charged GAG-binding C-terminal region, absent in most other chemokines. To examine whether the CXCL8 C-terminal peptide has a modulatory role in GAG binding during neutrophil recruitment, we synthesized the wild-type CXCL8 C-terminal [CXCL8 (54-72)] (Peptide 1), a peptide with a substitution of glutamic acid (E) 70 with lysine (K) (Peptide 2) to increase positive charge; and also, a scrambled sequence peptide (Peptide 3). Surface plasmon resonance showed that Peptide 1, corresponding to the core CXCL8 GAG-binding region, binds to GAG but Peptide 2 binding was detected at lower concentrations. In the absence of cellular GAG, the peptides did not affect CXCL8-induced calcium signalling or neutrophil chemotaxis along a diffusion gradient, suggesting no effect on GPCR binding. All peptides equally inhibited neutrophil adhesion to endothelial cells under physiological flow conditions. Peptide 2, with its greater positive charge and binding to polyanionic GAG, inhibited CXCL8-induced neutrophil transendothelial migration. Our studies suggest that the E70K CXCL8 peptide, may serve as a lead molecule for further development of therapeutic inhibitors of neutrophil-mediated inflammation based on modulation of chemokine-GAG binding.


Assuntos
Adesão Celular/imunologia , Movimento Celular/imunologia , Células Endoteliais/imunologia , Interleucina-8/imunologia , Neutrófilos/imunologia , Células Endoteliais/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Neutrófilos/patologia , Peptídeos/imunologia
18.
BMC Nephrol ; 20(1): 125, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30971227

RESUMO

BACKGROUND: There are limited long-term outcome data in eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with eculizumab. METHODS: Patients with aHUS who participated in any of five parent eculizumab trials and received at least one eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. RESULTS: Among 93 patients (0-80 years of age), 51 (55%) remained on eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated eculizumab had similar baseline clinical characteristics to patients who remained on eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged < 18 years at diagnosis, with identified genetic/autoimmune complement abnormalities, or history of multiple TMAs prior to eculizumab initiation. The safety profile was consistent with previous studies. Three definite and one possible meningococcal infections related to eculizumab were reported and resolved with treatment. Three deaths unrelated to eculizumab were reported. CONCLUSIONS: The current study confirms the efficacy and safety of eculizumab in aHUS, particularly with regard to long-term renal function and TMA events. Pediatric age at disease onset and presence of genetic or autoimmune complement abnormalities are risk factors for TMA events off treatment. Overall, patients who discontinue eculizumab may be at risk for additional TMA manifestations and renal function decreases. Discontinuation of eculizumab, with careful monitoring, is an option in select patients with consideration of patient preference, organ function normalization, and risk factors for relapse, including mutational analysis, age of onset, and history of multiple TMA episodes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01522170 , January 31, 2012.


Assuntos
Anticorpos Monoclonais Humanizados , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Efeitos Adversos de Longa Duração , Microangiopatias Trombóticas , Adolescente , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Síndrome Hemolítico-Urêmica Atípica/complicações , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/epidemiologia , Criança , Inativadores do Complemento/administração & dosagem , Inativadores do Complemento/efeitos adversos , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Cooperação Internacional , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/epidemiologia , Efeitos Adversos de Longa Duração/etiologia , Masculino , Conduta do Tratamento Medicamentoso , Avaliação de Processos e Resultados em Cuidados de Saúde , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/epidemiologia , Microangiopatias Trombóticas/etiologia
19.
Clin Kidney J ; 12(2): 196-205, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30976396

RESUMO

Background: Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods: In five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated. Results: Of 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment. Conclusions: As expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.

20.
Transplantation ; 103(4): e64-e73, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30907855

RESUMO

Fibrosis is a universal finding in chronic allograft dysfunction, and it is characterized by an accumulation of extracellular matrix. The precise source of the myofibroblasts responsible for matrix deposition is not understood, and pharmacological strategies for prevention or treatment of fibrosis remain limited. One source of myofibroblasts in fibrosis is an endothelial-to-mesenchymal transition (EndMT), a process first described in heart development and involving endothelial cells undergoing a phenotypic change to become more like mesenchymal cells. Recently, lineage tracing of endothelial cells in mouse models allowed studies of EndMT in vivo and reported 27% to 35% of myofibroblasts involved in cardiac fibrosis and 16% of isolated fibroblasts in bleomycin-induced pulmonary fibrosis to be of endothelial origin. Over the past decade, mature microRNAs (miRNAs) have increasingly been described as key regulators of biological processes through repression or degradation of targeted mRNA. The stability and abundance of miRNAs in body fluids make them attractive as potential biomarkers, and progress is being made in developing miRNA targeted therapeutics. In this review, we will discuss the evidence of miRNA regulation of EndMT from in vitro and in vivo studies and the potential relevance of this to heart, lung, and kidney allograft dysfunction.


Assuntos
Células Endoteliais/patologia , Mesoderma/patologia , MicroRNAs/fisiologia , Transplante Homólogo/efeitos adversos , Animais , Doença Crônica , Fibrose , Humanos , Rim/patologia , Miocárdio/patologia , Miofibroblastos/patologia , Fibrose Pulmonar/etiologia , Fator de Crescimento Transformador beta/fisiologia
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