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1.
Diabetologia ; 67(7): 1283-1294, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38647650

RESUMO

AIMS/HYPOTHESIS: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. METHODS: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. RESULTS: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). CONCLUSIONS/INTERPRETATION: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes.


Assuntos
Diabetes Mellitus Tipo 2 , Adesão à Medicação , Espectrometria de Massas em Tandem , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/urina , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Cromatografia Líquida/métodos , Doenças Cardiovasculares/urina , Doenças Cardiovasculares/tratamento farmacológico , Estudos de Coortes , Rim/metabolismo , Rim/fisiopatologia , Rim/efeitos dos fármacos , Hipoglicemiantes/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Espectrometria de Massa com Cromatografia Líquida
2.
Ren Fail ; 46(1): 2282709, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38682163

RESUMO

Budapest Nephrology School (BNS) could have celebrated its 30th event if it had not been interrupted by COVID pandemic for a few years. Yet, the organization of 27th BNS in August 2023 resumed its successful and traditional activities at Semmelweis University, in the beautiful central European city of Budapest. In over two decades, BNS has faithfully adapted to the changes and developments of medical science and clinical nephrology, the fact which has kept it unique and attractive for nephrologists from across the globe. With such a long history and representing the top international professors of nephrology, BNS has proved to be a successful one-week, in-person refreshing course which has attracted over 1600 medical doctors from more than 60 countries. It has well served as an academic meeting point suitable for networking and exchange of up-to-date knowledge presented by the best international experts in nephrology. The dedication and focus of these experts on education, research and patient care represent the very concept of translational medicine. The invaluable experience of the past 27 years has set the standards for BNS to contribute to the evolution of translational nephrology in Europe in the next decade.


Assuntos
Nefrologia , Nefrologia/história , Humanos , Hungria , História do Século XX , História do Século XXI , COVID-19/epidemiologia , Faculdades de Medicina/história
3.
Kidney Blood Press Res ; 48(1): 165-174, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37015210

RESUMO

INTRODUCTION: Type 2 diabetes and its complications represent a huge burden to public health. With this prospective, observational cohort study, we aimed to estimate and to compare the incidence rate (IR) of renal and cardiovascular outcomes and all-cause mortality in patients with type 2 diabetes in different European countries. METHODS: The renal endpoint was a composite of a sustained decline in estimated GFR of at least 40%, a sustained increase in albuminuria of at least 30% including a transition in albuminuria class, progression to kidney failure with replacement therapy, or death from renal causes. The cardiovascular endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: 3,131 participants from four European countries (Austria, Hungary, The Netherlands, and Scotland) with a median follow-up time of 4.4 years were included. IRs were adjusted for several risk factors including sex, age, estimated GFR, albuminuria, HbA1c, blood pressure, and duration of type 2 diabetes. Across countries, the adjusted IR for the renal endpoint was significantly higher in Hungary and Austria, and the adjusted IR for the cardiovascular endpoint was significantly higher in Scotland and Austria. All-cause mortality was significantly higher in Scotland compared to all other countries. CONCLUSION: Our findings show how the longitudinal outcome of patients with type 2 diabetes varies significantly across European countries even after accounting for the distribution of underlying risk factors.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Infarto do Miocárdio , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Estudos Prospectivos , Albuminúria/complicações , Doenças Cardiovasculares/etiologia , Fatores de Risco , Europa (Continente)/epidemiologia , Taxa de Filtração Glomerular
4.
Kidney Int ; 102(2): 337-354, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35513123

RESUMO

Patients with chronic kidney disease and experimental animal models of kidney fibrosis manifest diverse progression rates. Genetic susceptibility may contribute to this diversity, but the causes remain largely unknown. We have previously described kidney fibrosis with a mild or severe phenotype in mice expressing transforming growth factor-beta1 (TGF-ß1) under the control of a mouse albumin promoter (Alb/TGF-ß1), on a mixed genetic background with CBAxC57Bl6 mice. Here, we aimed to examine how genetic background may influence kidney fibrosis in TGF-ß1 transgenic mice, and in the unilateral ureteral obstruction (UUO) and subtotal nephrectomy (SNX) mouse models. Congenic C57Bl6(B6)-TGFß and CBAxB6-TGFß (F1) transgenic mice were generated and survival, proteinuria, kidney histology, transcriptome and protein expressions were analyzed. We investigated the kidneys of B6 and CBA mice subjected to UUO and SNX, and the effects of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) neutralization on the fibrotic process. CBAxB6-TGFß mice developed severe kidney fibrosis and premature death, while B6-TGF-ß mice had mild fibrosis and prolonged survival. Kidney early growth response factor-2 (EGR2) and TIMP-1 expression were induced only in CBAxB6-TGFß mice. Similar strain-dependent early changes in EGR2 and TIMP-1 of mice subjected to UUO or SNX were observed. TIMP-1 neutralization in vivo hindered fibrosis both in transgenic mice and the SNX model. EGR2 over-expression in cultured HEK293 cells induced TIMP-1 while EGR2 silencing hindered TGF-ß induced TIMP-1 production in HK-2 cells and ureteral obstructed kidneys. Finally, EGR2 and TIMP1 was increased in human kidneys manifesting focal segmental glomerulosclerosis suggesting a correlation between animal studies and patient clinical settings. Thus, our observations demonstrate a strong relationship between genetic background and the progression of kidney fibrosis, which might involve early altered EGR2 and TIMP-1 response, but the relationship to patient genetics remains to be explored.


Assuntos
Proteína 2 de Resposta de Crescimento Precoce , Insuficiência Renal Crônica , Inibidor Tecidual de Metaloproteinase-1 , Obstrução Ureteral , Animais , Proteína 2 de Resposta de Crescimento Precoce/genética , Fibrose , Células HEK293 , Humanos , Rim/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Transgênicos , Insuficiência Renal Crônica/complicações , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismo
5.
Ren Fail ; 43(1): 1609-1620, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34882053

RESUMO

Hemodialysis reactions (HDRs) resemble complement-activation-related pseudoallergy (CARPA) to certain i.v. drugs, for which pigs provide a sensitive model. On this basis, to better understand the mechanism of human HDRs, we subjected pigs to hemodialysis using polysulfone (FX CorDiax 40, Fresenius) or cellulose triacetate (SureFlux-15UX, Nipro) dialyzers, or Dialysis exchange-set without membranes, as control. Experimental endpoints included typical biomarkers of porcine CARPA; pulmonary arterial pressure (PAP), blood cell counts, plasma sC5b-9 and thromboxane-B2 levels. Hemodialysis (60 min) was followed by reinfusion of extracorporeal blood into the circulation, and finally, an intravenous bolus injection of the complement activator zymosan. The data indicated low-extent steady rise of sC5b-9 along with transient leukopenia, secondary leukocytosis and thrombocytopenia in the two dialyzer groups, consistent with moderate complement activation. Surprisingly, small changes in baseline PAP and plasma thromboxane-B2 levels during hemodialysis switched into 30%-70% sharp rises in all three groups resulting in synchronous spikes within minutes after blood reinfusion. These observations suggest limited complement activation by dialyzer membranes, on which a membrane-independent second immune stimulus was superimposed, and caused pathophysiological changes also characteristic of HDRs. Thus, the porcine CARPA model raises the hypothesis that a second "hit" on anaphylatoxin-sensitized immune cells may be a key contributor to HDRs.


Assuntos
Ativação do Complemento/imunologia , Hipersensibilidade/imunologia , Membranas Artificiais , Diálise Renal , Animais , Biomarcadores/análise , Celulose/análogos & derivados , Modelos Animais de Doenças , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hemodinâmica , Polímeros , Sulfonas , Suínos , Zimosan/farmacologia
6.
Clin Nephrol ; 94(5): 237-244, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870146

RESUMO

INTRODUCTION: The implantation of acute or chronic vascular accesses for hemodialysis (HD) in end-stage kidney disease patients is a critical skill procedure for nephrologists, with an impact on short- and long-term outcomes of the modality and patient survival. Placement circumstances, however, may depend on the availability of technological support and will likely vary across the world. MATERIALS AND METHODS: We retrospectively reviewed our local experience with ultrasound-guided tunneled dialysis catheter (TDC) insertions but without access to fluoroscopic guidance. Data were available for 63 patients with TDCs placed by faculty nephrologists at the dialysis unit procedure rooms between March 2015 and February 2018. We reviewed circumstances of TDC placement, patient characteristics, and procedural outcomes. RESULTS: The mean age was 62 (± 41) years, and 46% of the patients were male. All TDC placements were technically successful and no major complications occurred. Most TDCs (52.8%) were a de novo placement. In the de novo patient group, there were 27 right-sided internal jugular vein (IJV) and 6 left-sided IJV cannulations. Blood pump flow was 284.6 (± 58) mL/min via the temporary catheter 1 month before and 316.7 (± 46) mL/min 1 month after TDC placement (p < 0.0001). The majority of catheter tips (63%) reached the right atrial placement position successfully. DISCUSSION: Technologically successful TDC placement can be performed without fluoroscopic tip guidance and result in improved access flows and dialysis efficacy when compared to temporary hemodialysis catheters.


Assuntos
Cateterismo Venoso Central/métodos , Cateteres de Demora , Fluoroscopia/métodos , Falência Renal Crônica/terapia , Diálise Renal/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Cateterismo Venoso Central/instrumentação , Cateteres de Demora/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Ultrassonografia de Intervenção , Adulto Jovem
7.
Kidney Int ; 96(6): 1381-1388, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679767

RESUMO

Clinical risk factors explain only a fraction of the variability of estimated glomerular filtration rate (eGFR) decline in people with type 2 diabetes. Cross-omics technologies by virtue of a wide spectrum screening of plasma samples have the potential to identify biomarkers for the refinement of prognosis in addition to clinical variables. Here we utilized proteomics, metabolomics and lipidomics panel assay measurements in baseline plasma samples from the multinational PROVALID study (PROspective cohort study in patients with type 2 diabetes mellitus for VALIDation of biomarkers) of patients with incident or early chronic kidney disease (median follow-up 35 months, median baseline eGFR 84 mL/min/1.73 m2, urine albumin-to-creatinine ratio 8.1 mg/g). In an accelerated case-control study, 258 individuals with a stable eGFR course (median eGFR change 0.1 mL/min/year) were compared to 223 individuals with a rapid eGFR decline (median eGFR decline -6.75 mL/min/year) using Bayesian multivariable logistic regression models to assess the discrimination of eGFR trajectories. The analysis included 402 candidate predictors and showed two protein markers (KIM-1, NTproBNP) to be relevant predictors of the eGFR trajectory with baseline eGFR being an important clinical covariate. The inclusion of metabolomic and lipidomic platforms did not improve discrimination substantially. Predictions using all available variables were statistically indistinguishable from predictions using only KIM-1 and baseline eGFR (area under the receiver operating characteristic curve 0.63). Thus, the discrimination of eGFR trajectories in patients with incident or early diabetic kidney disease and maintained baseline eGFR was modest and the protein marker KIM-1 was the most important predictor.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Taxa de Filtração Glomerular , Receptor Celular 1 do Vírus da Hepatite A/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Insuficiência Renal Crônica/sangue , Idoso , Teorema de Bayes , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
8.
Ren Fail ; 41(1): 434-438, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162993

RESUMO

Objectives: The successful implantation of peritoneal dialysis (PD) catheters is a critical skill procedure with the potential to impact both the short- and long-term success of renal replacement therapy and the patients' survival. Methods: We retrospectively reviewed our single-center experience with nephrologist-placed minimally invasive, double-cuffed PD catheters (PDCs). Results: The recruitment period was March 2014 through December 2015. The follow-up period lasted until 2016. The mean age of the subjects was 60 ± 18 years and indications for the PD were diuretic resistant acutely decompensated chronic heart failure in seven patients (47%) and end-stage renal disease in eight (53%) patients. Comorbid conditions included diabetes (27%), ischemic heart disease (47%), advanced liver failure (27%), and a history of hypertension (73%). The cohort had a high mortality with five subjects only in severe heart failure group (33%) passing away during the index hospitalization; of the rest, two (13%) had heart transplantation, three (20%) changed modality to hemodialysis, and only five (33%) continued with maintenance PD beyond 1 month. Acute technical complications within the first month were infrequent: one catheter (6%) had drainage problems and one (6%) was lost due to extrusion. There were no serious complications (e.g., organ damage, peritonitis, etc.). Conclusions: In selected cases, particularly in severe diuretic refractory heart failure, PDC placement placed by a nephrologist is feasible with a low rate of complications even in a low-volume center setting. The catheters we placed were all functioning with only minor complications and PD could be started immediately.


Assuntos
Cateterismo/métodos , Cateteres de Demora/efeitos adversos , Insuficiência Cardíaca/terapia , Falência Renal Crônica/terapia , Diálise Peritoneal/instrumentação , Idoso , Cateterismo/efeitos adversos , Cateterismo/instrumentação , Estudos de Viabilidade , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Hungria , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Nefrologistas , Diálise Peritoneal/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
9.
Ren Fail ; 41(1): 440-445, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31162990

RESUMO

Objectives: Diffuse enlargements of arteriovenous dialysis fistulas customarily attributed to either excessive arterial inflow or central outflow stenosis. The relationship between volume status and clinically enlarged (arteriovenous) fistula (CEF) formation in end-stage renal disease (ESRD) patients is not well understood. Methods: We assessed the pre-dialysis bioimpedance spectroscopy-measured percentage of overhydration (OH%) in 13 prevalent dialysis patients with CEF development and negative angiography and compared the results with those of 52 control dialysis patients (CONTR). All patients were prevalent ESRD patients receiving thrice-weekly maintenance hemodiafiltration at an academic outpatient dialysis unit. Results: 10/13 CEF patients had OH% ≥15% as compared to 20/52 control patients (Chi square p: .02). The degree of OH% was 20.2 ± 7.4% among the CEF vs. 14.4 ± 7.1% in the control group (Student's t-test p: .01), representing 4.2 ± 3.2 vs. 2.8 ± 1.6 L of excess fluid pre-dialysis (p: .03). Patients with CEF development took an average of 1.7 ± 1.4 vs. 0.8 ± 0.8 (p: .002) antihypertensive medications compared to the CONTR patients, yet their blood pressure was higher: 156/91 vs. 141/78 mmHg (systolic/diastolic p: .03<.0001). We found no difference in fistula vintage, body mass index, age, diabetes status, or diuretic use. The odds ratio of having a CEF in patients with ≥15% OH status was 5.3 (95% CI: 1.3-21.7; p: .01), the Number Needed to Harm with overhydration was 4. Conclusions: There is an association between bioimpedance spectroscopy-measured overhydrated clinical state and the presence of CEF; either as an increased volume capacitance or as a potential cause.


Assuntos
Derivação Arteriovenosa Cirúrgica/efeitos adversos , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Desequilíbrio Hidroeletrolítico/diagnóstico , Adulto , Idoso , Estudos de Casos e Controles , Impedância Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/métodos , Desequilíbrio Hidroeletrolítico/complicações
10.
Molecules ; 24(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505853

RESUMO

Complement (C) activation can underlie the infusion reactions to liposomes and other nanoparticle-based medicines, a hypersensitivity syndrome that can be partially reproduced in animal models. However, the sensitivities and manifestations substantially differ in different species, and C activation may not be the only cause of pathophysiological changes. In order to map the species variation of C-dependent and -independent pseudoallergy (CARPA/CIPA), here we used known C activators and C activator liposomes to compare their acute hemodynamic, hematological, and biochemical effects in rats. These C activators were cobra venom factor (CVF), zymosan, AmBisome (at 2 doses), its amphotericin B-free vehicle (AmBisombo), and a PEGylated cholesterol-containing liposome (PEG-2000-chol), all having different powers to activate C in rat blood. The pathophysiological endpoints measured were blood pressure, leukocyte and platelet counts, and plasma thromboxane B2, while C activation was assessed by C3 consumption using the Pan-Specific C3 assay. The results showed strong linear correlation between C activation and systemic hypotension, pointing to a causal role of C activation in the hemodynamic changes. The observed thrombocytopenia and leukopenia followed by leukocytosis also correlated with C3 conversion in case of C activators, but not necessarily with C activation by liposomes. These findings are consistent with the double hit hypothesis of hypersensitivity reactions (HSRs), inasmuch as strong C activation can fully account for all symptoms of HSRs, but in case of no-, or weak C activators, the pathophysiological response, if any, is likely to involve other activation pathways.


Assuntos
Ativação do Complemento/efeitos dos fármacos , Síndrome de Hipersensibilidade a Medicamentos/tratamento farmacológico , Leucocitose/sangue , Lipossomos/farmacologia , Anfotericina B/química , Anfotericina B/farmacologia , Animais , Colesterol/química , Convertases de Complemento C3-C5/química , Convertases de Complemento C3-C5/farmacologia , Proteínas do Sistema Complemento/química , Proteínas do Sistema Complemento/metabolismo , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Síndrome de Hipersensibilidade a Medicamentos/patologia , Venenos Elapídicos/química , Venenos Elapídicos/farmacologia , Humanos , Hipotensão/sangue , Hipotensão/induzido quimicamente , Leucocitose/induzido quimicamente , Leucopenia/sangue , Leucopenia/induzido quimicamente , Lipossomos/química , Nanopartículas/química , Polietilenoglicóis/química , Ratos , Trombocitopenia/sangue , Trombocitopenia/induzido quimicamente , Zimosan/química , Zimosan/farmacologia
11.
Kidney Blood Press Res ; 43(1): 181-190, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29466797

RESUMO

BACKGROUND/AIMS: The prevalence of diabetes mellitus type 2 and kidney disease in these patients varies widely between European countries. METHODS: In addition to store bio-samples the "Prospective cohort study in patients with type 2 diabetes mellitus for validation of biomarkers" collects information on history, physical status, laboratory measurements and medication in 4000 patients with diabetes mellitus type 2, being taken care of at the primary level of healthcare in 5 European countries (Austria, Hungary, Netherlands, Poland and Scotland). Next to comparing the rate of loss of eGFR between the countries, a further objective of the PROVALID study is to determine the 5-year cumulative incidence of renal and cardiovascular outcomes. RESULTS: The mean age of the population recruited is 62.9±10 years, 54.6% are male and the mean BMI is 30.9±5.4 kg/m2. Metabolic control (median HBA1c 6.8 % (6.2; 7.5)) is achieved via administration of metformin in 67.4% of the patients and insulin in 30.3%. Median systolic and diastolic blood pressure at recruitment is 135 (125; 146) and 80 (72; 85) mmHg, 65.4% of subjects received RAAS blocking agents. Mean eGFR is 80.7±29.2 ml/min/1.73m2 and median baseline albumin/creatinine ratio 8.3 mg (IQR: 3.8 and 25.1). CONCLUSION: PROVALID will provide information on incidence and progression of renal and cardiovascular disease and therapy in patients with type 2 diabetes mellitus in different European countries. Thus, in contrast to many other cohort studies we will be able to associate national clinical practise pattern with outcome in this highly vulnerable patient population.


Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Idoso , Doenças Cardiovasculares/etiologia , Protocolos Clínicos , Estudos de Coortes , Diabetes Mellitus Tipo 2/epidemiologia , Europa (Continente) , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/etiologia , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Estudos Prospectivos
12.
Orv Hetil ; 159(26): 1041-1054, 2018 Jul.
Artigo em Húngaro | MEDLINE | ID: mdl-29936859

RESUMO

Semmelweis finally achieved results from his persistent research work. Those being the scientific analysis of clinical statistical data and his animal experiments, which recognized the dreadful disease of puerperal fever and its prevention. "He not only discovered the real cause of puerperal fever but he also created antiseptic prophylaxis, which he introduced in obstetrics and laid the foundations of modern surgery (asepsis). The theory and practice of asepsis stemmed from the discovery of the etiology of puerperal fever and therefore originating from the genius idea of Semmelweis. The discoveries of bacteriology by Lister, Pasteur and Koch only provided a scientific proof of the intuitive statements of Semmelweis." Semmelweis was a pioneer of clinical etiological research whose findings were aggressively disapproved by his colleagues due to earlier medical misunderstandings. Semmelweis is given due respect by posterity as a remuneration, to all the bitterness that he had suffered throughout his life. Semmelweis is considered the savior of mothers and infants. The Hungarian nation is very proud of him as he is one of our models whose oeuvre is acknowledged not only in Hungary but throughout the world. The message of his short, tragic yet effective life is eternal. The figure of Ignác Semmelweis is depicted as a statue and is placed in Chicago among the statues of the most innovative doctors and health care professionals of the world. The statue of Semmelweis is next to the statues of Louis Pasteur and Wilhelm Conrad Röntgen. "Semmelweis reflex" is a new expression which appeared and spread in English speaking countries. The word does not relate to a medical phenomenon but describes a social phenomenon when experts or the whole society automatically rejects discoveries and new recognitions without examination or justification. This phenomenon frequently occurs, even in our times. Orv Hetil. 2018; 159(26): 1041-1054.


Assuntos
Docentes de Medicina/história , Obstetrícia/história , Médicos/história , Feminino , História do Século XIX , Humanos , Gravidez , Infecção Puerperal/história
13.
Kidney Blood Press Res ; 42(1): 109-122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28359068

RESUMO

BACKGROUND/AIMS: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (pro)renin receptor ((P)RR) blockade and angiotensin converting enzyme (ACE) inhibition on the progression of diabetic nephropathy in rats. METHODS: Diabetes (DM) was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (P)RR blocker "handle region" decoy peptide (HRP, 0,1 mg/kg/day) or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day) and grouped as follows: 1. Control (n=10); 2. DM (n=8); 3. DM+HRP (n=6); 4. DM+Q (n=10); 5. DM+Q+HRP (n=10). Renal functional parameters, histology and gene expressions were evaluated. RESULTS: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2) phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-ß1 expression and ERK(1/2) phosphorylation to the same extent. CONCLUSION: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2) phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Renina/uso terapêutico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Diabetes Mellitus Experimental , Interações Medicamentosas , Quimioterapia Combinada , Rim/efeitos dos fármacos , Rim/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Quinapril , Ratos , Ratos Sprague-Dawley , Renina/farmacologia , Tetra-Hidroisoquinolinas/farmacologia
14.
BMC Nephrol ; 18(1): 209, 2017 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-28673338

RESUMO

BACKGROUND: Although TGF-ß and the transcription factor Egr-1 play an important role in both kidney fibrosis and in response to acute changes of renal medullary osmolarity, their role under sustained hypo- or hyperosmolar conditions has not been elucidated. We investigated the effects of chronic hypertonicity and hypotonicity on the renal medullary TGF-ß and Egr-1 expression. METHODS: Male adult Sprague Dawley rats (n = 6/group) were treated with 15 mg/day furosemide, or the rats were water restricted to 15 ml/200 g body weight per day. Control rats had free access to water and rodent chow. Kidneys were harvested after 5 days of treament. In cultured inner medullary collecting duct (IMCD) cells, osmolarity was increased from 330 mOsm to 900 mOsm over 6 days. Analyses were performed at 330, 600 and 900 mOsm. RESULTS: Urine osmolarity has not changed due to furosemide treatment but increased 2-fold after water restriction (p < 0.05). Gene expression of TGF-ß and Egr-1 increased by 1.9-fold and 7-fold in the hypertonic medulla, respectively (p < 0.05), accompanied by 6-fold and 2-fold increased c-Fos and TIMP-1 expression, respectively (p < 0.05) and positive immunostaining for TGF-ß and Egr-1 (p < 0.05). Similarly, hyperosmolarity led to overexpression of TGF-ß and Egr-1 mRNA in IMCD cells (2.5-fold and 3.5-fold increase from 330 to 900 mOsm, respectively (p < 0.05)) accompanied by significant c-Fos and c-Jun overexpressions (p < 0.01), and increased Col3a1 and Col4a1 mRNA expression. CONCLUSION: We conclude that both TGF-ß and Egr-1 are upregulated by sustained hyperosmolarity in the rat renal medulla, and it favors the expression of extracellular matrix components.


Assuntos
Ingestão de Líquidos/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Medula Renal/metabolismo , Fator de Crescimento Transformador beta1/biossíntese , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce/genética , Expressão Gênica , Medula Renal/citologia , Masculino , Concentração Osmolar , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/genética
15.
BMC Nephrol ; 18(1): 76, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28231769

RESUMO

BACKGROUND: The early identification of patients with ANCA-associated vasculitis (AAV) who are at increased risk for inferior clinical outcome at the time of diagnosis might help to optimize the immunosuppressive therapy. In this study we wanted to determine the predictive value of simple clinical characteristics, which may be applicable for early risk-stratification of patients with AAV. METHODS: We retrospectively analyzed the outcome of 101 consecutive patients with AAV receiving a protocolized immunosuppressive therapy. Baseline Birmingham Vasculitis Activity Score (BVAS) and non-vasculitic comorbidities were computed, then predictors of early (<90 days) and late (>90 days) mortality, infectious death, relapse and end stage kidney disease (ESKD) were evaluated. RESULTS: The baseline comorbidity score independently predicted early mortality (HR 1.622, CI 1.006-2.614), and showed association with infectious mortality (HR 2.056, CI 1.247-3.392). Patients with BVAS at or above median (=21) had worse early mortality in univariable analysis (HR 3.57, CI 1.039-12.243) (p = 0.031), and had more frequent relapses (p = 0.01) compared to patients with BVAS below median. CONCLUSIONS: Assessing baseline comorbidities, beside clinical indices characterizing the severity and extension of AAV, might help clinicians in risk-stratification of patients. Future prospective studies are needed to investigate whether therapies based on risk-stratification could improve both short term and long term survival.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Infecções/mortalidade , Falência Renal Crônica/epidemiologia , Idoso , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/tratamento farmacológico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Comorbidade , Feminino , Humanos , Imunossupressores/uso terapêutico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
16.
Am J Physiol Heart Circ Physiol ; 310(9): H1055-63, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-26993222

RESUMO

Endothelial-mesenchymal transition (EndMT) is an important mechanism during organ development and in certain pathological conditions. For example, EndMT contributes to myofibroblast formation during organ fibrosis, and it has been identified as an important source of cancer-associated fibroblasts, facilitating tumor progression. Recently, EndMT was proposed to modulate endothelial function during intravasation and extravasation of metastatic tumor cells. Evidence suggests that endothelial cells are not passive actors during transendothelial migration (TEM) of cancer cells, as there are profound changes in endothelial junctional protein expression, signaling, permeability, and contractility. This review describes these alterations in endothelial characteristics during TEM of metastatic tumor cells and discusses them in the context of EndMT. EndMT could play an important role during metastatic intravasation and extravasation, a novel hypothesis that may lead to new therapeutic approaches to tackle metastatic disease.


Assuntos
Células Endoteliais/patologia , Transição Epitelial-Mesenquimal , Neoplasias/patologia , Migração Transendotelial e Transepitelial , Animais , Comunicação Celular , Células Endoteliais/metabolismo , Humanos , Metástase Neoplásica , Neoplasias/metabolismo , Transdução de Sinais , Microambiente Tumoral
17.
Nephrol Dial Transplant ; 30 Suppl 4: iv1-5, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26209731

RESUMO

Renal disease is prevalent in patients with diabetes mellitus type 2. Aggressive metabolic control and lowering of systemic and/or intraglomerular blood pressure are effective interventions but not without side effects. Thus a better, early identification of patients at risk for incidence or progression to end-stage renal failure by the use of new, validated biomarkers is highly desirable. In the majority of patients, hypertension and hyperglycaemia are pathogenetically important pathways for the progression of renal disease. Nonetheless even aggressive therapy targeting these factors does not eliminate the risk of end-stage renal failure and experimental evidence suggests that many other pathways (e.g. tubulointerstitial hypoxia or inflammation etc.) also contribute. As their individual importance might vary from patient to patient, interventions which interfere are likely not to be therapeutically effective in all subjects. In this situation, an option to preserve the statistical power of clinical trials is to rely on biomarkers that reflect individual pathophysiology. In current clinical practice, albuminuria is the biomarker that has been best evaluated to guide stratified/personalized therapy but there is a clear need to expand our diagnostic abilities.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias/diagnóstico , Nefropatias/terapia , Diagnóstico Precoce , Humanos , Nefropatias/etiologia
18.
Am J Pathol ; 182(2): 388-400, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23178076

RESUMO

During progressive tubulointerstitial fibrosis, renal tubular epithelial cells transform into α-smooth muscle actin (SMA)-expressing myofibroblasts via epithelial-to-mesenchymal transition (EMT). SMA expression is regulated by transforming growth factor (TGF)-ß1 and cell contact disruption, through signaling events targeting the serum response factor-myocardin-related transcription factor (MRTF) complex. MRTFs are important regulators of fibrosis, tumor cell invasion, and metastasis. Consistent with the role of MRTFs in tumor progression, suppressor of cancer cell invasion (SCAI) was recently identified as a negative regulator of MRTF. Herein, we studied the role of SCAI in a fibrotic EMT model established on LLC-PK1 cells. SCAI overexpression prevented SMA promoter activation induced by TGF-ß1. When co-expressed, it inhibited the stimulatory effects of MRTF-A, MRTF-B or the constitutive active forms of RhoA, Rac1, or Cdc42 on the SMA promoter. SCAI interfered with TGF-ß1-induced SMA, connective tissue growth factor, and calponin protein expression; it rescued TGF-ß1-induced E-cadherin down-regulation. IHC studies on human kidneys showed that SCAI expression is reduced during fibrosis. Kidneys of diabetic rats and mice with unilateral ureteral obstruction depicted significant loss of SCAI expression. In parallel with the decrease of SCAI protein expression, diabetic rat and mouse kidneys with unilateral ureteral obstruction showed SMA expression, as evidenced by using Western blot analysis. Finally, TGF-ß1 treatment of LLC-PK1 cells attenuated SCAI protein expression. These data suggest that SCAI is a novel transcriptional cofactor that regulates EMT and renal fibrosis.


Assuntos
Transição Epitelial-Mesenquimal , Rim/metabolismo , Rim/patologia , Fatores de Transcrição/metabolismo , Actinas/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Humanos , Células LLC-PK1 , Camundongos , Proteínas dos Microfilamentos/metabolismo , Regiões Promotoras Genéticas/genética , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Suínos , Fatores de Transcrição/genética , Fator de Crescimento Transformador beta1/farmacologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Calponinas
19.
Nephrol Dial Transplant ; 28(7): 1751-61, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23203993

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is characterized by podocyte damage and increased phosphodiesterase-5 (PDE-5) activity-exacerbating nitric oxide (NO)-cyclic 3',5' guanosine monophosphate (cGMP) pathway dysfunction. It has been shown that PDE-5 inhibition ameliorates DN. The role of podocytes in this mechanism remains unclear. We investigated how selective PDE-5 inhibition influences podocyte damage in streptozotocin (STZ) diabetic rats. METHODS: Male Sprague-Dawley rats (250-300 g) were injected with STZ and divided into two groups: (i) STZ control (non-treated, STZ, n=6) and (ii) STZ+vardenafil treatment (10 mg/kg/day, STZ-Vard, n=8). Non-diabetic rats served as negative controls (Control, n=7). Following 8 weeks of treatment, immunohistochemical and molecular analysis of the kidneys were performed. RESULTS: Diabetic rats had proteinuria, increased renal transforming growth factor (TGF)-ß1 expression and podocyte damage when compared with controls. Vardenafil treatment resulted in preserved podocyte cGMP levels, less proteinuria, reduced renal TGF-ß1 expression, desmin immunostaining in podocytes and restored both nephrin and podocin mRNA expression. Diabetes led to increased glomerular nitrotyrosine formation and renal neuronal nitric oxide synthase and endothelial nitric oxide synthase mRNA expression, but vardenafil did not influence these parameters. CONCLUSIONS: Our data suggest that a dysfunctional NO-cGMP pathway exacerbates podocyte damage in diabetes. In conclusion, vardenafil treatment preserves podocyte function and reduces glomerular damage, which indicates therapeutic potential in patients with DN.


Assuntos
GMP Cíclico/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/prevenção & controle , Imidazóis/farmacologia , Inibidores da Fosfodiesterase 5/farmacologia , Piperazinas/farmacologia , Podócitos/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/etiologia , Proteinúria/metabolismo , Proteinúria/prevenção & controle , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sulfonas/farmacologia , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Triazinas/farmacologia , Dicloridrato de Vardenafila
20.
Fogorv Sz ; 106(2): 53-9, 2013 Jun.
Artigo em Húngaro | MEDLINE | ID: mdl-24344561

RESUMO

VEGF induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability in many organs. Nevertheless, we have only limited information about its role on gingival hemodynamics, especially in venules. Therefor the aim of this study was to assess the acute circulatory effects of VEGF on rat gingival venules by means of the following protocol. Wister rats (n=63) were devided into five study groups after anesthesia; each animal received 10 microl of experimental solution dripped onto the lower interincisal gingiva. The groups included: 1) saline control (after the experiment, gingiva was excised for VEGF receptor 2 [VEGFR2] immunohistochemistry); 2) VEGF (0.1, 1, 10, or 50 microg/ml); 3) VEGF2 receptor antagonist 5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methyl-phenol-hydrochloride (ZM323881; 20 microg/ml); 4) ZM323881 (20 microg/ml) followed by VEGF application (50 microg/ml after 15 minutes); and 5) VEGF (10 microg/ml), these rats were premedicated with nitric oxide (NO) synthase blocker (NG-nitro-L-arginine-methyl-ester [L-NAME]; 1 mg/ml in drinking water) for 1 week before the experiment. Changes in gingival superficial venule diameter were measured by vital microscopy prior to and 1, 5, 15, 30, and 60 minutes after the administration of the experimental solutions. According to our findings, VEGF dose-dependently increased the venular diameter compared to saline. ZM323881 alone did not cause any alteration. Premedication with ZM323881 or L-NAME decreased the dilatory effects of VEGF. Occassionally moderate VEGFR2 immunohistochemical labeling was observed in the wall components of the venules. Concluding our results we can say, that there is no remarkable VEGF production under physiologic circumstances in rat gingiva, but VEGF is able to increase gingival blood flow through the activation of VEGF2 receptors and consequent NO release.


Assuntos
Inibidores Enzimáticos/farmacologia , Gengiva/irrigação sanguínea , NG-Nitroarginina Metil Éster/farmacologia , Quinazolinas/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Vasodilatação/efeitos dos fármacos , Vênulas/efeitos dos fármacos , Animais , Permeabilidade Capilar/efeitos dos fármacos , Relação Dose-Resposta a Droga , Imuno-Histoquímica , Masculino , Neovascularização Patológica , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/efeitos dos fármacos
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