L’insuffisance rénale chronique (IRC) est associée à une diminution de la clairance métabolique des médicaments résultant en partie de l’inhibition des cytochromes P450 (CYP450) et des enzymes de phase II, notamment la N-acétyltransférase 2 (NAT2), tel que démontré chez le rat. Nous avons précédemment démontré le rôle de l'hormone parathyroïdienne (PTH) dans la diminution des CYP450 hépatiques chez le rat souffrant d’IRC. Toutefois, l’étude des mécanismes sous-jacents pouvant être facilitée par l’utilisation de souris transgéniques, l’objectif de cette étude consiste à confirmer ces résultats dans un modèle murin. D’abord, afin de valider ce modèle expérimental, une IRC a été induite par néphrectomie subtotale 3/4 chez des souris C57BL/6, puis l’expression protéique et génique des CYP450 et de la Nat2 hépatiques a été étudiée. Les résultats indiquent que l’IRC induit effectivement une diminution d’expression de ces enzymes dans un modèle murin. Ensuite, des souris mutantes pour le gène codant la PTH (PTH-/-) et les souris correspondantes de type sauvage (PTH+/+) ont été néphrectomisées, puis l’expression protéique et génique des CYP450 hépatiques a été analysée. Si la PTH est responsable de la diminution du CYP450 en situation d’IRC, les souris PTH-/- atteintes d’IRC ne devraient présenter aucune baisse d’expression. Les résultats obtenus pour les souris PTH-/- ne peuvent être interprétés, puisque chez les souris PTH+/+ atteintes d'IRC, le CYP450 hépatique est inchangé par rapport aux souris PTH+/+ témoins. Des expériences supplémentaires seront requises afin de déterminer si la régulation à la baisse du CYP450 précédemment observée est contrecarrée par l’absence de PTH. / Chronic renal failure (CRF) is associated with a decrease in the metabolic clearance of drugs, which is partly due to a reduced expression of cytochrome P450 (CYP450) and phase II enzymes, namely N-acetyltransferase 2 (NAT2). This phenomenon has been shown in the rat. We have previously demonstrated the role of parathyroid hormone (PTH) in CYP450 down-regulation in rats with CRF. However, the study of mechanisms underlying the down-regulation of CYP450 by PTH should be confirmed with the use of knockout mice. The aim of this study was, therefore, to confirm these results in a murine model. Firstly, to validate this experimental model, CRF was produced in C57BL/6 mice using the 3/4 subtotal nephrectomy. Protein and mRNA levels of hepatic CYP450 and Nat2 were then analyzed. The results showed that CRF down-regulates these enzymes, as previously observed in the rat. Finally, PTH-null mice (PTH-/-) and their corresponding wild type (PTH+/+) were nephrectomized in order to analyze protein and mRNA expression of hepatic CYP450. If PTH is responsible for the decrease of CYP450 in the presence of CRF, then PTH-/- mice with CRF should not show any reduction in CYP450 expression compared to controls. The results concerning the PTH-/- mice could not be interpreted because PTH+/+ mice with CRF did not show any significant difference of CYP450 expression when compared to PTH+/+ controls. Thus, additional experiments must be conducted in order to determine the role of PTH in CYP450 down-regulation in CRF mice.

Introduction: Nous avons déjà montré que l’insuffisance rénale chronique (IRC) entraîne une régulation négative du cytochrome P450 (CYP450) dans le foie et l’intestin de rat. La présente étude cherche à déterminer l’effet de l’IRC sur l’expression des enzymes du CYP450 dans le cerveau de rat. L’expression génique, protéique ainsi que l’activité des isoenzymes du CYP450 ont été analysées dans différentes régions du cerveau (hippocampe, cervelet, cortex et parenchyme cérébral) afin de déterminer l’effet de l’insuffisance rénale chronique sur le métabolisme cérébral des médicaments par le CYP450. Méthodes: Le cerveau entier de rats atteints d’IRC (induite par une néphrectomie sub-totale 5/6) et de rats témoins (laparotomie blanche) a été disséqué en 4 parties (cortex, cervelet, hippocampe et parenchyme cérébral). L’expression protéique et celle de l’ARNm des isoformes 1A, 2C11, 2D, 3A et 4A du cytochrome P450 a été étudiée respectivement par immunobuvardage de type Western et PCR en Temps Réel. L’activité du CYP3A a été mesurée par le métabolisme du DFB en DFH sur des préparations de microsomes de cerveau. Une technique de culture cellulaire d’astrocytes a été mise au point et a permis d’évaluer l’expression des enzymes dans ces cellules suite à l’incubation des astrocytes avec le sérum de rats atteints d’insuffisance rénale chronique. Résultats: Chez les rats atteints d’IRC, les niveaux géniques de CYP1A, 2C et 3A sont diminués d’au moins 40% (p < 0,05) dans presque toutes les parties étudiées. Les niveaux d’ARNm du CYP2D demeurent inchangés. De plus, une diminution significative d’au moins 45% (p < 0,05) de l’expression protéique des CYP1A, 2C et 3A est observée dans presque toutes les structures étudiées. L’activité enzymatique de CYP3A est diminuée significativement dans le cerveau de rats IRC, ainsi que l’expression des enzymes du CYP2C11 dans les astrocytes en culture lorsqu’incubés avec du sérum de rat urémique. Conclusions: Ces études démontrent que le cerveau est également affecté par l’IRC. Ceci se traduit par une diminution de l’expression protéique, génique, ainsi que de l’activité des enzymes du CYP450. Cette diminution pourrait expliquer une augmentation des effets secondaires dans le système nerveux central en IRC. / Background: It has been shown that chronic renal failure (CRF) is associated with a downregulation of liver and intestinal cytochrome P450 (CYP450) in the rat. The present study aimed to investigate the repercussions of CRF on Brain. CYP450 isoenzymes mRNA and protein expression, as well as activity in different brain regions (cortex, cerebellum, hippocampus, and rest of brain parenchyma), have been studied in order to determine the effects of CRF on cerebral drug metabolism by CYP450. Methods: The entire brain of CRF rats (induced by 5/6th nephrectomy) and control rats (sham laparotomy) was dissected into 4 parts (cortex, cerebellum, hippocampus, and rest of brain parenchyma). Protein and mRNA expression of CYP1A, CYP2C, CYP2D, CYP3A, and CYP4A were assessed by Western Blot assay and Real Time PCR, respectively. CYP3A activity was assessed using DFB metabolism into DFH in brain microsomal preparation. Protein and mRNA expression were also assessed in cultured astrocytes incubated with serum from CRF rats. Results: In CRF rats, mRNA levels of CYP1A, CYP2C, and CYP3A were decreased significantly by at least 40% (p < 0.05) in almost all studied brain regions. Protein expression of these isoforms was decreased by at least 45% (p < 0.05) in almost all structures. A significant decrease in CYP3A activity was observed in the brain. The incubation of astrocytes with CRF sera induced a decrease in the protein and mRNA expression of the CYP2C11. Conclusions: CRF is associated with a decrease in some major drug-metabolizing enzymes, which could explain an increase in bioavailability of drugs in the brain.

L’insuffisance rénale chronique (IRC) est caractérisée par de multiples déséquilibres homéostatiques tels que la résistance à l’insuline. Peu d’études se sont intéressées aux mécanismes sous-jacents à cette résistance à l’insuline en IRC. De plus, il est méconnu si cette résistance à l’insuline peut mener au développement d’un diabète de type II chez des patients prédisposés. Dans un modèle d’IRC, le rat Sprague-Dawley (CD) néphrectomisé 5/6e, on observe une corrélation entre la gravité de l’atteinte rénale, évaluée par la créatinine sérique, et l’hyperglycémie, évaluée par la fructosamine sérique (R2 = 0.6982, p < 0.0001). Cependant, cet état hyperglycémique n’est pas observable lors d’une glycémie à jeun. Lors d’un test de tolérance au glucose, on observe une plus grande élévation de la glycémie (AUC 1.25 fois, p < 0.0001) chez le rat atteint d’IRC. Par contre, la sécrétion d’insuline au cours de ce même test n’augmente pas significativement (AUC ≈ 1.30 fois, N.S.) en comparaison aux rats témoins. Malgré une élévation des taux d’insuline en IRC suivant un bolus de glucose, les tissus périphériques ne montrent pas d’augmentation de la captation du glucose sanguin suggérant un défaut d’expression et/ou de fonction des transporteurs de glucose chez ces rats. En effet, on observe une diminution de ces transporteurs dans divers tissus impliqués dans le métabolisme du glucose tel que le foie (≈ 0.60 fois, p < 0.01) et le muscle (GLUT1 0.73 fois, p < 0.05; GLUT4 0.69 fois, p < 0.01). En conséquence, une diminution significative du transport insulinodépendant du glucose est observable dans le muscle des rats atteint d’IRC (≈ 0.63 fois, p < 0.0001). Puisque les muscles sont responsables de la majorité de la captation insulinodépendante du glucose, la diminution de l’expression du GLUT4 pourrait être associée à la résistance à l’insuline observée en IRC. La modulation de l’expression des transporteurs de glucose pourrait être à l’origine de la résistance à l’insuline en IRC. Cela dit, d’autres mécanismes peuvent aussi être impliqués. En dépit de cette importante perturbation du transport du glucose, nous n’avons pas observé de cas de diabète de type II chez le rat CD atteint d’IRC. Dans un modèle de rat atteint d’un syndrome métabolique, le rat Zucker Leprfa/fa, l’IRC provoque une forte hyperglycémie à jeun (1.5 fois, p < 0.0001). De plus, l’IRC chez le rat Zucker provoque une réponse glycémique (AUC 1.80 fois, p < 0.0001) exagérée lors d’un test de tolérance au glucose. Une forte résistance à l’insuline est mesurée au niveau des muscles puisque la dose usuelle d’insuline (2mU/mL) n’est pas suffisante pour stimuler la captation du glucose chez le rat Zucker atteint d’IRC. De plus, une modulation similaire des transporteurs de glucose peut être observée chez ces deux espèces. Par contre, environ 30% (p < 0.001) des rats Zucker atteints d’IRC avaient une glycosurie. L’IRC en soi ne mènerait donc pas au développement d’un diabète de type II. Par contre, lorsqu’une résistance à l’insuline est présente antérieurement au développement d’une IRC, cela pourrait précipiter l’apparition d’un diabète de type II chez ces patients prédisposés. / Chronic renal failure (CRF) is characterized by multiple homeostasis imbalances such as insulin resistance. However, few studies addressed the underlying mechanisms of the insulin resistance in CRF. Moreover, it is not known if the insulin resistance in CRF could lead to type II diabetes in predisposed patients. In 5/6th nephrectomised Sprague-Dawley (CD) rat model of CRF, we observed a correlation between the severity of the renal injury, evaluated by the serum creatinine level, and the hyperglycaemia, evaluated by the serum fructosamine level (R2 = 0.6982, p < 0.0001). However, this hyperglycemia is not observed on fasting. During a glucose tolerance test, we noticed an increase of the glycaemia in CRF rats (AUC 1.25 fold, p < 0.0001) comparing to controls. Insulin secretion of CRF rats was not significantly higher (AUC ≈1.30 fold, N.S.) during glucose challenge. Interestingly, despite more increase in insulin levels in CRF rats following a glucose bolus, the peripheral tissues did not show any increase in blood glucose uptake suggesting a defect in expression and/or function of glucose transporters in these rats. Indeed, we observed decreased expression of glucose transporters in the liver (≈0.60 fold, p < 0.01) and muscles (GLUT1 0.73 fold, p < 0.05 and GLUT4 0.69 fold, p < 0.01). Accordingly, there was a significant reduction in the insulin-dependent glucose uptake in the muscles of CRF rats compared to controls (≈0.63 fold, p < 0.0001). Since muscles are responsible for the majority of insulin-sensitive glucose transport, downregulation of GLUT4 could be associated with the insulin resistance observed in CRF. The modulation of the expression of several glucose transporters may contribute to insulin resistance in CRF, but other mechanisms could also be implicated. Despite this important perturbation of glucose transport, we did not observed any case of type II diabetes in our CD rat model. In a rat model of metabolic syndrome, the Zucker Leprfa/fa, CRF causes a strong hyperglycemia on fasting (1.5 fold, p < 0.0001). Furthermore, CRF Zucker showed an exacerbated glycemic response (AUC 1.80 fold, p < 0.0001) during glucose challenge. A strong insulin resistance in muscle was measured as the usual insulin dose (2mU/mL) was not enough to stimulate glucose uptake in Zucker rats with CRF. The same modulation of glucose transporters in the peripheral tissues was observed in both rat models. As opposed to CD rats, ≈30% (p < 0.05) of CRF Zucker rats’ showed presence of glucose in their urine. CRF by itself won’t lead to type II diabetes. However, when insulin resistance is already present when developing CRF, it could precipitate the onset of type II diabetes among these patients.

Malaria remains one of the world's major health problems, especially in developing countries. A better understanding of the pathology and pathophysiology of severe malaria is key to develop new treatments. Different approaches have been used in malaria research including the in vitro co-culture models with endothelial cells and both murine and simian animal models. However these are open to controversy due to disagreement on their representativeness of human disease. Using human post-mortem tissue in malaria research is another important approach but is practically challenging, limiting the availability of post mortem samples from malaria patients. The work in this thesis had two main themes. First I examined the role of the endothelial signalling Angiopoetin-Tie-2 receptor pathway in malaria. Ang-2 has been shown to be a significant biomarker of severe and fatal malaria. I examined the tissue specific expression of proteins from this pathway in post-mortem brain tissues from fatal malaria cases, but found no difference between cerebral malaria and non-cerebral malaria cases. Ang-2 correlated with the severity of malaria in these patients. An attempt to examine the interaction of hypoxia and the Ang-Tie-2 pathway in vitro using a co-culture model of human brain endothelial cells was unsuccessful due to contamination of the cell line. The second part of the thesis aimed to utilise molecular pathology techniques including miRNA and whole-genome microarrays. I have shown for the first time that these can be successfully applied to human post-mortem tissue in malaria. First I used archival tissues to examine the microRNA signature in the kidney of patients with malaria associated renal failure. Second I optimised a protocol to preserve post mortem tissue for molecular pathology, from an autopsy study in Mozambique. Using the subsequent total mRNA transcriptomic data and bioinformatics analysis this work has expanded our knowledge of differential gene expression and the families of genes which are dysregulated in the brain in response to malaria infection.

The diploma thesis deals with the emotional experience of patients with chronic renal failure. It aims to explore positive and negative emotional experiences, the presence of depressive and anxiety symptoms, the degree of anger and alexithymia in patients with chronic renal failure undergoing hemodialysis. The theoretical part summarizes previously published theoretical knowledge in this area and the empirical part describes the statistical measurement and comparison of selected variables of emotional experience in the research sample. The theoretical part is divided into 4 chapters, the first of them deals with the medical aspects of chronic renal failure and its treatment. The second chapter deals with the coping with illness, defines psychological aspects of chronic disease and describes the patient's subjective perception of the disease and attitudes towards the disease. The third chapter summarizes the definitions of emotions and emotional experience and defines the most respected theories of emotion. The fourth chapter describes the emotional experiences of illness, factors affecting the emotional experience of illness and deals with depression, anxiety, anger and alexithymia, at the end focuses on current research in this area. The empirical part is devoted to the empirical investigation of...

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Made available in DSpace on 2016-01-26T12:51:30Z (GMT). No. of bitstreams: 1 heloisacaldas_tese.pdf: 13961449 bytes, checksum: adc041656d053c466bd2f0851119388c (MD5) Previous issue date: 2011-07-26 / Chronic renal failure (CRF) is characterized by progressive and irreversible loss of renal function and its treatment generates significant public spending for maintenance and care of patients on dialysis. Stem cell (SC) therapy, in its potential for treatment of chronic diseases, may be a promising strategy for repairing the damage from or slowing the progression of CRF. There are questions about cell type, quantity of cells, method and ideal place for deployment of SC and the role it plays in the repair of renal parenchyma. Objective: 1) To evaluate the effect of infusion of bone marrow derived cells (BMDC) in the treatment of experimental CRF; 2) Evaluate the combined effect of SC and biomaterial (BM) in the progression of CRF and study the effect of this therapy in different stages of CRF; 3) Evaluate the development of techniques for isolation and cultivation of human umbilical cord blood (HUCB) mesenchymal cells. Methods: Article 1: We used the 5/6 mass reduction model to induce experimental CRF. Kidney function was measured at the beginning of the experiment and 60 and 120 days after the surgery; Article 2: Animals were subdivided as to the amount of renal parenchyma injured (5/6 or 2/3), the use of BM as a scaffold to cell implantation, and cell type used (mononuclear or mesenchymal cells). Renal function was evaluated on days 0, 45, and 90 after surgery. Histological and immunohistochemical analyses were done in all groups at the end of the study; Article 3: Ten samples of HUCB were used and two different procedures for cultivation of mesenchymal stem cells (MSC) were tested: without Ficoll-Paque density gradient, to obtain nucleated cells; with Ficoll-Paque density gradient, for obtaining mononuclear cells. Results: Article 1: CRF progression analysis showed that treatment with BMDC significantly reduced the rate of decline of creatinine clearance (Clcr) when compared with the control group; Article 2:Treated animals showed significantly lower increases in serum creatinine and 24 hour proteinuria, and higher increases in Clcr after 90 days when compared to control animals in both models of CRF; Article 3: The MSC in culture from the method without Ficoll-Paque density gradient maintained growth forming confluent cell foci. Conclusions: Article 1: Progression of CRF can be delayed by injection of BMDC in the renal parenchyma; Article 2: a) Use of SC combined with BM can be an alternative way to administer BMDC; b) Cell therapy seems to be most effective when administered in less severe stages of CRF; Article 3: Nucleated cells without using Ficoll-Paque density gradient showed more efficiency in the cultivation of MSC from HUCB when compared with the procedure employing Ficoll-Paque density gradient / A insuficiência renal crônica (IRC) é caracterizada pela perda progressiva e irreversível da função renal e seu tratamento gera um gasto público significativo para manutenção de pacientes em tratamento dialítico. A terapia com células-tronco (CT), pelo seu potencial de tratamento das doenças crônicas, pode ser uma estratégia promissora para reparar ou retardar a progressão da IRC. Existem dúvidas sobre o tipo celular, a quantidade de células, o método e local ideal para implantação das CT e o papel por elas desempenhado na reparação do parênquima renal. Objetivos: 1) avaliar o efeito da infusão de células derivadas da medula óssea (CDMO) no tratamento da IRC experimental; 2) avaliar o efeito combinado das CT e biomaterial (BM) na progressão da IRC e estudar o efeito dessa terapia em diferentes estágios da IRC; 3) Avaliar o desenvolvimento de técnicas de isolamento e cultivo de células mesenquimais do sangue de cordão umbilical humano (SCU). Métodos: artigo 1: usamos o modelo de redução de massa 5/6 para induzir a IRC experimental. Função renal foi medida no início do experimento e 60 e 120 dias depois da cirurgia; artigo 2: animais foram subdivididos conforme a quantidade de parênquima renal lesado (5/6 ou 2/3), o uso de BM como arcabouço para o implante celular e o tipo de células utilizado (célula mononuclear ou mesenquimal). A função renal foi avaliada nos dias 0, 45 e 90 após cirurgia. Análise histológica e imunohistoquimica foram realizadas em todos os grupos ao final do estudo; artigo 3: Foram utilizadas dez amostras de SCU e testados dois diferentes procedimentos para cultivo de células-tronco mesenquimal (CTM): sem gradiente de densidade Ficoll-Paque, para obtenção de células nucleadas; por gradiente de densidade Ficoll-Paque, para obtenção de células mononucleares. Resultados: artigo 1: Análises da progressão da IRC mostraram que o tratamento com CDMO reduziu significativamente a taxa de declínio do clearance ( Clcr) quando comparados com o grupo controle; artigo 2: animais tratados apresentaram aumentos significativamente menores de creatinina sérica, proteinúria e Clcr maiores após 90 dias, quando comparado aos animais controles em ambos os modelos de IRC; artigo 3: as CTM em cultura provenientes do método sem gradiente de densidade Ficoll- Paque mantiveram o crescimento formando focos confluentes de células. Conclusões: artigo 1: a progressão da IRC pode ser retardada pela injeção de CDMO no parênquima renal; artigo 2: a) utilização da CT combinada com o BM pode ser uma via alternativa para administrar a CTMO; b) terapia celular parece ser mais eficaz quando administrada em estágios menos graves da IRC; artigo 3: As células nucleadas sem uso do gradiente de densidade Ficoll-Paque mostraram mais eficiente para o cultivo de CTM do SCU quando comparado ao procedimento com gradiente de densidade Ficoll-Paque.

Made available in DSpace on 2016-01-26T12:51:16Z (GMT). No. of bitstreams: 1 marielza_dissert_parte 1.pdf: 600568 bytes, checksum: 0107e3e73118e6ec5de58894e7163c10 (MD5) Previous issue date: 2004-04-27 / Technological improvements in dialysis have contributed for the increased survival of chronic renal patients, however, undergoing dialysis treatment for an indeterminate time might interfere in the quality of life of these patients. This study was aimed at evaluating the quality of life of chronic renal patients undergoing hemodialysis and identifying the activities that might have a negative impact on their quality of life. This is a descriptive and exploratory study, including 125 chronic renal patients undergoing hemodialysis (74 men and 51 women), mean age 53.1±14.6 years, mean time on hemodialysis 28.5±23 months. The generic SF-36 quality of life questionnaire and a semi-structured interview were used as data collection instruments. Data was subject to a descriptive statistical analysis, the chi-squared test, Pearson s correlation coefficient and the proportion comparison test, with a significance level of 5%. The results showed impaired quality of life of the patients, with lower scores for physical aspects dimensions (32.3±11.3), emotional aspects (46.1±16.3) and vitality (48.7±7.3). Quality of life variables regarding genders did not have a significant difference. There was a negative correlation between time on hemodialysis and physical component (r=-0.75, p<0.001), indicating that the longer the time on hemodialysis the lower are the scores found for this component and there was no significant correlation between time on hemodialysis and mental component (r=-0.29). Physical and recreational activities were the most affected in the global sample and in the sample stratified by gender. There was a negative correlation between time on hemodialysis and daily activities: work (p=0.0014), domestic activities (p=0.0014) and practical activities (0.0459). Data have shown impairment in several of the analyzed quality of life aspects in chronic renal patients undergoing hemodialysis and have pointed out that daily physical and recreational activities were the most affected ones. Our results have allowed the conclusion that there were no evidences of statistically significant differences in quality of life compared to gender; time on hemodialysis correlated with quality of life and daily activities had a negative correlation with physical component and work, domestic and practical activities. These results are important predictive factors to improve quality of life parameters in these patients. / Os avanços tecnológicos na área de diálise contribuíram para o aumento da sobrevida dos renais crônicos, entretanto, a permanência por tempo indeterminado em tratamento dialítico pode interferir na qualidade de vida destes pacientes. Este estudo teve como objetivo avaliar a qualidade de vida de pacientes renais crônicos em tratamento de hemodiálise e identificar as atividades cotidianas, que podem comprometer na qualidade de vida. Trata-se de estudo descritivo e exploratório, onde foram pesquisados 125 pacientes renais crônicos em tratamento de hemodiálise (74 homens e 51 mulheres), com média de idade 53,114,6 anos, tempo médio de hemodiálise de 28,523 meses. Utilizou como instrumentos de coleta de dados o questionário genérico de qualidade de vida SF-36 e a entrevista semi-estruturada. Os dados foram submetidos a análise estatística descritiva, o teste qui-quadrado, o coeficiente de correlação de Pearson e o teste de comparação de proporções, efetuados ao nível de 5% de significância. Os resultados constataram prejuízo na qualidade de vida dos pacientes, demostrando menores escores nos domínios dos aspectos fisicos (32 3+11 3), aspectos emocionais (46,11 6,3) e vitalidade (48,77,3). As variáveis de qualidade de vida em relação ao sexo não apresentou diferença significante. Verificou-se correlação negativa entre tempo de hemodiálise e componente físico (r = -0,75, p< 0,001), indicando que quanto maior o tempo de hemodiálise mais baixos são os valores encontrados deste componente e não houve correlação sígnificante entre tempo de hemodiálise e componente mental (r = -0,29). As atividades corporais e recreativas foram as mais comprometidas tanto na amostra global quanto na estratificada por sexo. Observou-se correlação negativa entre tempo de hemodiálise e as atividades cotidianas: trabalho (p=0,001 4), atividades domésticas (p= 0,0014) e atividades práticas (0,0459). Nota de Resumo Os dados evidenciaram o comprometimento em vários domíníos analisados da qualidade de vida dos renais crônicos em hemodiálise e identificaram que as atividades cotidianas corporais e recreativas foram as mais afetadas. Os resultados permitiram concluir: que não houve evidências de diferença estatisticamente significantes da qualidade de vida em relação ao sexo; houve diferença estatisticamente significante quanto as atividades cotidianas; o tempo de hemodiálise correlacionado com a qualidade de vida e atividades cotidianas apresentou correlação negativa no componente físico e nas atividades do trabalho, domestica e prática respectivamente Estes valores são importantes fatores preditivos para a melhora dos parâmetros de qualidade de vida destes pacientes.

Made available in DSpace on 2016-01-26T12:51:25Z (GMT). No. of bitstreams: 1 joaofernandopicollodeoliveira_dissert.pdf: 2216002 bytes, checksum: 172981ec9e4daa13d8e1e6872337867d (MD5) Previous issue date: 2008-12-10 / Nephrotoxicity is the main adverse effect of aminoglycoside use. There are few information about its prevalence and risk factor in intensive care unit patients. Objectives: To assess the prevalence, mortality and risk factors for aminoglycoside nephrotoxicity in ICU patients. Casuistic and Method: In order to assess the prevalence of, and risk factors for aminoglycoside nephrotoxicity in the ICU, 360 consecutive patients starting aminoglycoside therapy in the ICU with a baseline calculated GFR (cGFR) &#8805;30 ml/min/1.73 m2 were evaluated. Results: Of them, 209 (58%) developed aminoglycoside-induced nephrotoxicity (AKI, decrease in cGFR >20% from baseline), while 151 did not (non-AKI). Both groups had similar baseline cGFR. The AKI group developed a lower cGFR nadir (45 ± 27 vs. 79 ± 39 ml/min/1.73 m2, p<0.001), was older (56 ± 18 y vs. 52 ± 19 y, p=0.033), had a higher prevalence of diabetes (19.6% vs. 9.3%, p=0.007), used other nephrotoxic drugs (51% vs. 38%, p=0.024) and iodinated contrast more frequently (18% vs. 8%, p=0.0054), showed higher prevalence of hypotension (63% vs. 44%, p=0.0003), shock (56% vs. 31%, p<0.0001), and jaundice (19% vs. 8%, p=0.0036). Mortality was 44.5% in the AKI and 29.1% in the non-AKI groups (p=0.0031). A logistic regression model identified as significant (p<0.05) independent factors affecting aminoglycoside-induced nephrotoxicity baseline cGFR<60 ml/min/1.73 m2 (OR 0.42), diabetes (OR 2.13), simultaneous use of other nephrotoxins (OR 1.61) or iodinated contrast (OR 2.13), and hypotension (OR 1.83). Conclusion: The AKI was frequent among ICU patients using aminoglycoside, and it was associated with high mortality. The presence of diabetes, hypotension, simultaneous use of other nephrotoxic drugs, and iodinated contrast were independent risk factors for the development of aminoglycoside-induced nephrotoxicity. / Nefrotoxicidade é a principal complicação do uso de aminoglicosídeos. Existem poucas informações sobre a prevalência e os fatores de risco para nefrotoxicidade por aminoglicosídeos em paciente internados em unidades de terapia intensiva. Objetivos: Avaliar a prevalência, a mortalidade e os fatores de risco para nefrotoxicidade por aminoglicosídeos em pacientes internados em Unidade de Terapia Intensiva geral. Casuística e Métodos: Foram avaliados a prevalência, os fatores de risco e a mortalidade da nefrotoxicidade por aminoglicosídeo de 360 pacientes internados em terapia intensiva com filtração glomerular calculada por fórmula (MDRD, RFG) basal &#8805;30ml/min/ 1,73m2, que iniciaram o uso do antibiótico na terapia intensiva; nefrotoxicidade foi definida como queda >20% na RFG em relação ao RFG basal. Resultados: Entre os pacientes estudados 209 (58%) desenvolveram nefrotoxicidade (IRA) e 151 não alteraram a função renal (não IRA). Ambos os grupos (média±desvio padrão) tinham RFG basal similar (89&#61617;42 ml/min/ 1,73m2 no grupo IRA versus 84±42 ml/min/ 1,73m2 no grupo não IRA). O grupo IRA teve menor nadir de RFG (45±27 ml/min/ 1,73m2 versus 79±39 ml/min/ 1,73m2, p<0,001), idade maior (56&#61617;18 anos versus 52&#61617;19 anos, p=0,033), maior prevalência de diabetes (19,6% versus 9,3%, p=0,007), uso simultâneo mais freqüente de outras drogas nefrotóxicas (51% versus 38%, p=0,024) e contraste (18% versus 8%, p=0,0054), maior prevalência de hipovolemia (44% versus 27%, p=0,001), hipotensão (63% versus 44%, p=0,0003), choque (56% versus 31%, p<0,0001) e icterícia (19% versus 8%, p=0,0036). A mortalidade foi 44,5% no grupo IRA e 29,1% no grupo não IRA (p=0,0031). A análise por regressão logística identificou como fatores de risco independente para a nefrotoxicidade por aminoglicosídeo, RFG basal <60ml/min/1,73m2 [OR 0,42 (IC 95% 0,24-0,72, p=0,02)], diabetes [OR 2,13 (IC 95% 1,01-4,49, p=0,046)], uso simultâneo de outras drogas nefrotóxicas [OR 1,61 (IC 95% 1,00-2,59, p=0,048)], uso de contraste iodado [OR 2,13 (IC 95% 1,02-4,43, p=0,043)] e hipotensão [OR 1,83 (IC 95% 1,14-2,94, p=0,012)]. Conclusões: Nefrotoxicidade por aminoglicosídeo foi freqüente e associada a alta mortalidade em pacientes de UTI. A presença de diabetes, hipotensão, uso simultâneo de outras drogas nefrotóxicas e contraste iodado foram fatores de risco independentes para o desenvolvimento de nefrotoxicidade.

A insuficiência renal crônica (IRC) é caracterizada por alterações glomerulares secundárias aos mecanismos adaptativos ocasionados por perda de néfrons funcionantes. Alterações na hemodinâmica glomerular, proliferação celular, influxo de células inflamatórias, desequilíbrio na síntese de proteínas da matriz extracelular glomerular (MECG) e perda da seletividade de carga e/ou tamanho da membrana basal glomerular têm sido apontados como mecanismos envolvidos na expansão mesangial e conseqüente glomeruloesclerose. A participação dos hormônios sexuais na função renal e na evolução da insuficiência renal crônica tem sido sugerida. Os glicosaminoglicanos, especialmente o heparan sulfato (HS), têm sido associados à seletividade glomerular de macromoléculas. O remodelamento podocitário precoce e a proteinuria (PTN) se relacionam com a progressão da IRC. Neste contexto, o acúmulo de MECG, proliferação de miofibroblastos e PTN têm sido apontados como mediadores precoces que precedem as lesões glomerulares e túbulo-intersticiais. Neste estudo, avaliamos as alterações renais precoces (30 dias de IRC) gênero-dependentes em ratos (M) e ratas (F) Wistar submetidos à redução de 5/6 da massa renal (IRC) e à castração (c). Os animais foram divididos em 10 grupos: Controles (C) (CM, CF, CMc, CFc) e sham (CM sham, CF sham); e aqueles submetidos à nefrectomia 5/6: IRCM, IRCF, IRCMc, IRCFc. Os animais foram castrados com 5 semanas e submetidos à nefrectomia 5/6 com 7 semanas de idade. Resultados significativos mostraram que os machos com IRC apresentaram maior PTN, acompanhada de maior comprometimento mesangial, imunomarcação positiva para &#945;-actina e maior concentração de heparan sulfato (HS) comparados com as fêmeas IRC (p<0,05). Estas alterações foram reduzidas nos machos castrados. A análise da morfologia podocitária mostrou raras regiões onde ocorreram alterações podocitárias nos grupos IRC. O conjunto de dados sugere que o hormônio masculino pode participar na manutenção do equilíbrio mesangial e que a PTN participa do processo de expansão mesangial. Adicionalmente, a maior concentração de HS nos machos com IRC sugere que durante o processo de remodelação da MEG, tenha ocorrido geração de HS de novo, funcionalmente defeituoso, comprometendo a barreira de filtração glomerular, corroborando com a perda de seletividade da mesma e, contribuindo para maior PTN neste grupo. As fêmeas com IRC apresentaram alterações mais discretas quando comparadas aos machos; apresentaram decréscimo de HS renal associado a PTN e a castração não alterou este perfil. Em resumo, a PTN ocorre precocemente na IRC, contribuindo para o desequilíbrio da MECG. Os mecanismos envolvidos nestes processos parecem sofrer influência dos hormônios sexuais; e os hormônios masculinos parecem agravar estas alterações, contribuindo possivelmente para um pior prognóstico da doença renal nos machos. / Chronic renal failure (CRF) is characterized by adaptive mechanisms secondary to the loss of functioning nephrons. Glomerular hemodynamics alterations, cellular proliferation, inflammatory cells influx, imbalance between synthesis and degradation of the glomerular extracellular matrix (GECM) and loss of charge and/or size selectivity of the glomerular basal membrane are pointed as mechanisms leading to mesangial expansion and glomerulosclerosis. Additionally, participation of gender related hormones on renal function and progression of CRF have been suggested. We evaluated the effect of castration in renal alterations in males (M) and females (F) Wistar rats, after 30 days of 5/6 reduction of renal mass (CRF). The animals were castrated (c) at 5 weeks old and 7 weeks old 5/6 and sham nephrectomy were done. Groups: Control (C) CM, CM sham, CMc, CF, CF sham, CFc, CRFM, CRFMc, CRFF, CRFFc. CRFM group showed higher proteinuria followed by increased mesangial expansion and &#945;-actin immunostaining. Concomitant higher concentration of heparan sulfate (HS) was also observed when compared to CRFF (p<0.05). These alterations were reduced in CRFMc group. Podocyte morphology analysis through electronic microscopy showed few disorders of foot processes in CRF groups Overall, CRFF group showed fewer alterations compared to males, and a reduction of HS was observed in association with PTN. Castration did not change this profile in female rats. Data suggest that male hormones may participate in the maintenance of the mesangial equilibrium and that PTN collaborated with the mesangial expansion process. Additionally, the higher concentration of HS in CRFM suggest that the remodeling process of the GECM, included a synthesis of de novo HS, that presented a functioning defect, compromising the glomerular filtration barrier and, ultimately corroborated with the loss of its selectivity and consequently with a higher PTN. This set of results leads us to conclude that PTN appears early in the course of CRF, may contribute to renal GECM imbalance and, the mechanisms involved in these processes seem to be influenced by gender-related hormones. In addition, male hormones seem to aggravate renal alterations contributing to a poor prognosis of CRF progression in male rats.