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.

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.

Esta tese trata sobre as (re)construções identitárias de homens ao se tornarem portadores da doença renal crônica e sobre suas relações com o cuidado. A doença é percebida como um construto cultural em sua conexão com gênero/masculinidade, ainda pouco visualizada nos estudos da área da saúde. O referencial teórico-metodológico que orienta as análises situa-se nos campos dos estudos culturais, de gênero, da enfermagem e da sociologia da saúde. Os objetivos foram compreender as trajetórias identitárias de homens doentes renais crônicos e entender como o gênero constitui e marca essas trajetórias, assim como descrever e problematizar as estratégias que homens doentes renais crônicos desenvolvem para lidar com a doença e com a nova identidade que assumem. Desenvolveu-se um trabalho de campo, utilizando alguns procedimentos de investigação etnográfica. Por sete meses, um grupo de nove homens foi acompanhado durante suas sessões de tratamento substitutivo renal, a hemodiálise: nos primeiros três meses, através da observação participante de todo o contexto da unidade renal e, posteriormente, mediante entrevistas em profundidade com pacientes e suas cuidadoras domiciliares. Assim, foi constituído e organizado o material empírico que possibilitou as análises deste estudo. Tal movimento analítico possibilitou descrever e problematizar o processo saúde/doença e seus efeitos na vida desses homens: as alterações corporais, os medos da morte e de depender da máquina, os riscos e as incertezas do tratamento, as perdas no trabalho e a reconfiguração de suas masculinidades. Foi possível, também, descrever e analisar os suportes que organizam, cuidam e governam suas vidas durante o processo de tornarem-se doentes, bem como os processos através dos quais eles se (re)constroem como homens, em sua nova identidade de doente renal crônico, com formas de cuidados de si e reorganização de vida, trabalho, relações e apegos. Como resultados, identificou-se que tais pacientes demoram a tomar consciência desse processo: sofrem, questionam-se, brigam consigo mesmos, com as pessoas próximas e com a máquina. A possibilidade da morte passa a estar sempre presente, por isso reorganizam suas vidas em torno de objetivos pequenos, alcançáveis em menos tempo. Voltam-se, então, para a família e para a clínica em que fazem seu tratamento, mas com dificuldades de se adaptar a esses espaços que acreditam não lhes pertencer. E, muito lentamente, vão (re)construindo suas identidades. / This thesis discusses the identity re-constructions of men to become chronic kidney disease patients and their relations with care. The disease is perceived as a cultural construct in its connection with gender/masculinity, still not frequent in health studies. The theoretical and methodological framework that guides the analysis is situated in the fields of cultural, gender, nursing and health sociology studies. The objectives were to understand the identity trajectories of men with chronic renal failure patients and to understand how gender constitute and mark these pathways, as well as describing and problematizing strategies these men develop to cope with illness and with the new identity they assume. It was developed a field work, using some ethnographic research procedures. For seven months, a group of nine men was accompanied during their sessions of renal substitutive treatment, hemodialysis: in the first three months, through participant observation of the entire context of renal unit, and later through interviews with patients and their home caregivers. Thus, it was formed and organizes the empirical material which allowed the analysis in this study. That analytic movement enabled to describe and to question the health/illness process and its effects on these men‟s lives: body changes, fear of death and depending on the machinery, risks and doubts of treatment, work losses and masculinities reconfiguration. It was also possible to report and analyze the supports which organize, take care and govern their lives during the process of becoming sick, as well as the process through which they re-construct themselves as men, in their new chronic renal patient identity, and other forms of self care and reorganization of life, work, relations and passions. As results, it was found that such patients are slow to realize this process: they suffer, question themselves, fight themselves, with close people and with the machine. The possibility of death becomes always present, so they reorganize their lives around small goals, reachable in less time. Then they return to family and to the clinic where their treatment occurs, but struggling to adapt to these spaces in which they do not believe to belong. And, very slowly, they re-construct their identities. / Esta tesis trata sobre las re(construcciones) identitarias de hombres cuando adquieren la enfermedad renal crónica y sobre sus relaciones con el cuidado. La enfermedad se percibe como un constructo cultural en su conexión con género/masculinidad, todavía poco visualizada en los estudios del área de la salud. El referencial teórico-metodológico que orienta los análisis se sitúa en los campos de los estudios culturales, de género, de la enfermería y de la sociología de la salud. Los objetivos fueron comprender las trayectorias identitarias de hombres con enfermedad renal crónica y entender cómo el género constituye y marca esas trayectorias, así como describir y problematizar las estrategias que hombres con enfermedad renal crónica desarrollan para enfrentar la enfermedad y la nueva identidad que asumen. Se desarrolló un trabajo de campo, utilizando algunos procedimientos de investigación etnográfica. Por siete meses se acompañó a un grupo de nueve hombres durante sus sesiones de terapia de reemplazo renal, la hemodiálisis: en los primeros tres meses, a través de la observación participante de todo el contexto de la unidad renal y, posteriormente, mediante entrevistas en profundidad con pacientes y sus cuidadoras domiciliares. Así se constituyó y organizo el material empírico que permitió los análisis de ese estudio. Tal movimiento analítico permitió describir y problematizar el proceso de salud/enfermedad y sus efectos en la vida de esos hombres: las alteraciones corporales, los miedos a la muerte y a depender de una máquina, los riesgos e incertidumbres del tratamiento, las pérdidas en el trabajo y la reconfiguración de sus masculinidades. Fue posible, además, describir y analizar los soportes que organizan, cuidan y gobiernan sus vidas durante el proceso de ponerse enfermos, así como los procesos a través de los que ellos se (re)construyen como hombres, en su nueva identidad de persona con enfermedad renal crónica, con formas de cuidados de sí y reorganización de vida, trabajo, relaciones y apegos. Como resultados, se identificó que tales pacientes tardan a concienciarse de ese proceso: sufren, se cuestionan, pelean consigo mismos, con las personas cercanas y con la máquina. La posibilidad de la muerte pasa a estar siempre presente, por eso reorganizan sus vidas alrededor de objetivos pequeños, alcanzables en menos tiempo. Se vuelven entonces a la familia y a la clínica en la que hacen su tratamiento, pero con dificultades de adaptarse a esos espacios que creen que no les pertenece. Y muy lentamente van (re)construyendo sus identidades.

Fibroblast growth factor-23 (FGF23) is a novel, bone-produced hormone that regulates renal phosphate (Pi) reabsorption and calcitriol metabolism. Disorders of mineral and bone metabolism, such as autosomal dominant hypophosphatemic rickets (ADHR) and hyperostosis-hyperphosphatemia syndrome (HHS), witness the importance of well-balanced serum levels of FGF23. Patients with chronic kidney disease (CKD) are highly morbid due to Pi retention/hyperphosphatemia and calcitriol deficiency, which lead to elevated serum levels of parathyroid hormone (PTH) and secondary hyperparathyroidism (sHPT). As a response to hyperphosphatemia, CKD patients have also remarkably high serum FGF23 levels, which are associated with cardiovascular risk factors and increased mortality in CKD. The overall aim of this dissertation was to discern a possible role of FGF23 in parathyroid biology. Our in vitro experiments on isolated bovine parathyroid cells demonstrate that FGF23 directly and dose-dependently suppresses the PTH production and secretion, while increasing the expression of the 25-hydroxyvitamin D3-activating enzyme 1α-hydroxylase. We investigated possible expressional changes in the FGF23 receptor co-factor Klotho in hyperparathyroid disorders and found that Klotho expression is decreased or absent and inversely correlated to serum calcium (Ca) in adenomas of primary HPT (pHPT). In the hyperplastic parathyroid glands of sHPT, Klotho expression declines in parallel with the kidney function and correlates with the glomerular filtration rate. Moreover, Klotho expression is suppressed by Ca and FGF23, increased by calcitriol, but unaffected by Pi and PTH in vitro. Finally, we identified a novel missense mutation in the gene encoding GALNT3, which is normally involved in the post-translational glycosylation of FGF23, as the cause of aberrant FGF23 processing in a patient with HHS. In summary, we provide evidence for a novel bone/parathyroid axis in which FGF23 functions as a direct, negative regulator of the PTH production. High extracellular Ca is a major determinant of the Klotho expression in pHPT, whereas the Klotho levels in sHPT may be attributed to a combination of the high FGF23 and Ca, and low calcitriol levels associated with CKD. Hence, the decreased Klotho expression in sHPT could explain the concomitantly high FGF23 and PTH levels, as well as the failure of FGF23 to prevent or mitigate the development of sHPT in CKD.

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.

Introduction : Les modèles murins sont grandement utilisés dans l’étude des maladies rénales et des pathologies associées. La concentration de la créatinine sérique est un bon indicateur de la filtration glomérulaire et en présence d’insuffisance rénale chronique (IRC), les concentrations de créatinine sérique (et la clairance) reflètent la sévérité de l’IRC. De plus, il a été démontré que l’IRC modifie le métabolisme des médicaments en diminuant l’activité et l’expression des enzymes hépatiques du cytochrome P450 (CYP450). Afin d’étudier la modulation du P450 par l’IRC avec un modèle murin et de confirmer nos résultats chez le rat, nous devons 1) développer un modèle d’IRC chez la souris, 2) mettre au point une technique de dosage des marqueurs de l’IRC et, 3) évaluer l’expression protéique du CYP450 en présence IRC. Matériel et Méthode : Trois modèles chirurgicaux d’IRC chez la souris ont été développés. Une méthode du dosage de la créatinine par chromatographie liquide à haute performance (CLHP) a été mise au point chez la souris et l’expression protéique du P450 a été mesurée par immunobuvardage de type Western. Résultats : Plusieurs paramètres de CLHP comme le pH, la concentration et le débit de la phase mobile modifient le pic d’élution et le temps de rétention de la créatinine. Concernant le modèle expérimental, on observe une perte de poids et une augmentation de la concentration plasmatique de la créatinine chez les souris avec une IRC. De plus, l’expression protéique de plusieurs isoformes du cytochrome P450 est modulée par l’IRC. Nous observons une diminution du CYP 2D de 42% (p < 0,01), du CYP 3A11 de 60% et du CYP 1A de 37% (p <0,01) par rapport aux souris témoins. On ne dénote aucun changement significatif au niveau de l’isoforme 2E1. Conclusion : Il est possible d’induire une insuffisance rénale chronique chez la souris suite à une néphrectomie. La technique de dosage de la créatinine par CLHP est précise et exacte et permet de caractériser la sévérité de l’IRC chez la souris. L’expression protéique du CYP450 est régulée à la baisse dans le foie des souris atteintes d’IRC. / Background: Mice models are widely used in renal studies. Seric creatinine concentration is used to evaluate glomerular filtration rate and is a good marker of chronic renal failure (CRF). It has been shown that CRF diminishes drug metabolism in the rat because of a downregulation of hepatic cytochrome P450 (CYP450) isoforms. To study CYP450 regulation in the mouse model, we needed to 1) develop a model of CRF in the mouse, 2) define a method of dosage of CRF markers, and 3) evaluate CYP450 protein expression in the liver of mice with CRF. Methods: Models of CRF were tested and sub-total nephrectomy was selected because of the efficacy and reproducibility to induce CRF. A high pressure liquid chromatography (HPLC) method for the dosage of creatinine in mice sera was developed. Liver protein expression of CYP1A1, CYP3A11, CYP2D and CYP2E1 was assessed by Western Blot analysis. Results: HPLC parameters such as pH, mobile phase concentration and flow rate modified the elution profile. Weight loss and high seric creatinine concentrations are seen in mice with CRF. Furthermore, protein expression of CYP1A, CYP3A11 and CYP2D was decreased in liver microsomes of mice with CRF by 37%, 60% and 42%, respectively (p<0.01) compared to sham-operated mice. We found no significant difference in the expression of CYP2E1. Conclusions: CRF models are reproducible in the mouse. The HPLC method for creatinine determination is precise and accurate, and can assess the severity of CRF. Hepatic protein expression of CYP450 is modulated in presence of CRF as in the rat.

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.

Made available in DSpace on 2014-12-17T14:46:50Z (GMT). No. of bitstreams: 1 SueniaSMX_DISSERT.pdf: 1506804 bytes, checksum: e19da1d457fc43b9cffcb6bedf264524 (MD5) Previous issue date: 2011-12-09 / Reconstruct, from listening, the life histories of a chronic renal patient, submitted to hemodialysis, is the objective of this investigation. How methodological procedure,we worked with oral history of life, ,according Meihy, within a qualitative approach. For this, we had the approval of the Ethics Committee in Research of Hospital Universit?rio Onofre Lopes (HUOL), under protocol no 591/2011. As instrument to approach the patient, we did interviews with open questions, conducted in the patient's house. There were five meetings, in which we hear his story, experiences and ways of coping during their course of illness and treatment. The analysis was based on the collaborator's narratives, anchored in studies dealing with oral history, of human subjectivity, highlighting the resilience, as indicated Cyrulnik. Her story leads us to conclude that despite the adversities of life and suffering, there is in humans, the strength to navigate the streams and be happy. This is the lesson that leaves us the collaborator this study. / Reconstruir, a partir da escuta, a trajet?ria de vida de uma paciente renal cr?nica, submetida ao tratamento hemodial?tico, constitui o objetivo desta investiga??o. Como procedimento metodol?gico, trabalhamos com a hist?ria oral de vida, conforme Meihy, dentro de uma abordagem qualitativa. Para isto, tivemos a aprova??o do Comit? de ?tica em Pesquisa, do Hospital Universit?rio Onofre Lopes (HUOL), sob protocolo de n?. 591/2011. Como instrumento de abordagem da paciente, fizemos entrevistas com quest?es abertas, realizadas na casa da paciente. Foram cinco encontros, nos quais escutamos sua hist?ria, experi?ncias e formas de enfrentamento, durante sua trajet?ria de adoecimento e tratamento. A an?lise foi pautada nas narrativas da colaboradora, ancorada em estudos que tratam da hist?ria oral, da subjetividade humana, com destaque para a resili?ncia, conforme assinala Cyrulnik. Sua hist?ria nos leva a concluir que, apesar das adversidades da vida e do sofrimento, existe, no ser humano, a for?a de navegar nas torrentes e conseguir ser feliz. Essa ? a li??o que nos lega a colaboradora deste estudo.

Introdução: A maioria dos distúrbios metabólicos presentes na doença renal crônica (DRC) resulta, principalmente, do acúmulo de produtos do metabolismo do nitrogênio presentes nos alimentos ricos em proteínas. Dietas hiperprotéicas estão associadas à hiperperfusão, hipertensão e hiperfiltração glomerular e, conseqüentemente, à progressão da DRC. A dietoterapia tem um papel importante no tratamento da DRC, consistindo, principalmente, na redução da oferta diária de proteínas. Objetivo: Verificar o efeito da intervenção dietoterápica no estado nutricional, na progressão da doença renal e nos parâmetros inflamatórios, lipídicos, estado oxidativo e níveis séricos de potássio, de pacientes com insuficiência renal crônica em fase pré-dialítica. Pacientes e Métodos: Foi realizado um estudo prospectivo randomizado controlado cruzado em pacientes com DRC Estágio IV, em atendimento ambulatorial. O estudo constou de dois grupos de pacientes com DRC em fase pré-dialítica, que seguiram dois esquemas dietoterápicos diferentes, durante seis semanas: 21 pacientes iniciaram com prescrição de dieta normoprotéica (1 g/kg/dia) e 20 com prescrição de dieta hipoprotéica (0,6 g/kg/dia). Após esse período, os grupos inverteram as dietas. Foram avaliados parâmetros dietéticos, bioquímicos e antropométricos no momento basal e após seis e doze semanas. Os dados foram analisados segundo a intenção de tratamento na análise de crossover e por adesão à dieta hipoprotéica. Utilizaramse testes ANOVA para medidas repetidas e correlação de Spearman. O nível de significância adotado foi o de P < 0,05. Resultados: Foram avaliados 41 pacientes. Apenas um paciente (2,4%) foi considerado desnutrido e 28 (68%) apresentaram sobrepeso ou obesidade. Dezessete pacientes (41,5%) foram considerados inflamados, de acordo com o nível de PCR. Houve baixa adesão à dieta hipoprotéica.Não se observou prejuízo no estado nutricional dos pacientes durante o seguimento de prescrição de dieta hipoprotéica. Nos pacientes não inflamados observou-se melhora nos parâmetros de função renal, ao passo que, nos inflamados, estes parâmetros apresentaram deterioração. Observaram-se correlações negativas significativas entre os níveis séricos de HDL-colesterol e creatinina; HDL-colesterol e IMC; e correlações positivas significativas entre colesterol-total e uréia; LDL-colesterol e uréia; PNA/kg e HDL, triglicerídios e tirosina; triglicerídios e fibrinogênio; triglicerídios e creatinina; uréia e albumina. Conclusões: A adesão à dieta hipoprotéica foi muito pequena. A dieta hipoprotéica não interferiu no estado nutricional. A presença de inflamação influenciou, negativamente, a evolução da função renal. O perfil lipídico esteve relacionado ao estado nutricional, aos fatores de progressão da DRC e à inflamação; a lipoperoxidação esteve associada aos níveis séricos de albumina. / Background: Most metabolic disorders presented by patients with chronic renal disease (CRD) are mainly a result of accumulation of products of nitrogen metabolism, present in protein rich foods. High protein diets are associated with hyperperfusion, hypertension and hyperfiltration of the glomeruli and, as a consequence, may accelerate the progression of CRF. Nutritional therapy plays an important role in CRF treatment, consisting mainly in reduction of daily protein intake. Objective: To verify the effect of nutrition therapy intervention on nutritional status, on renal disease progression and on inflammatory and lipid parameters, oxidative status and potassium serum levels in patients with chronic renal insufficiency in the pre dialysis period. Patients and Methods: A crossover controlled prospective, randomized study in outpatients with stage IV CRD was carried out. The study consisted in the follow up of two groups of patients with CRD in the pre dialysis period. By randomization 21 patients were started on a 1g protein/kg/day diet prescription and 20 patients on low protein diet (0.6g/kg/day). After six weeks diets were reversed between the two groups and followed for another six week period. Dietetic, biochemical and anthropometric parameters were assessed at baseline and after 6 and 12 weeks. Data were analyzed according to the intention to treat approach in the crossover analysis and by adherence to the low protein diet. ANOVA for repeated measures and Spearman´s correlation tests were used for statistical analysis. The significance level adopted was P < 0.05. Results: 41 patients were evaluated. Only one patient (2.4%) was considered undernourished and 28 patients (68%) presented either over weighted or obese. Seventeen patients (41.5%) were considered inflamed according to the level of C reactive protein (CRP). Low adherence to the low protein diet was observed. Damage on nutritional status was not observed on low protein diet. In non-inflamed patients an improvement on renal function parameters was observed, whereas in the inflamed ones these parameters presented deterioration. Significant negative correlations between HDL-cholesterol serum levels and creatinine, HDL-cholesterol and body mass index (BMI) were observed. Significant positive correlations were observed between total cholesterol and urea, LDL-cholesterol and urea, PNA/kg and HDL, triglycerides and tyrosine, triglycerides and fibrinogen, triglycerides and creatinine, urea and albumin. Conclusions: Patients adhered poorly to low protein diets. Low protein diet did not influence the nutritional status. Presence of inflammation influenced negatively the evolution of renal function. The lipid profile was related to the nutritional status, to the progression factors of CRF and to inflammation. Lipoperoxidation was associated to serum levels of albumin.

Esta tese trata sobre as (re)construções identitárias de homens ao se tornarem portadores da doença renal crônica e sobre suas relações com o cuidado. A doença é percebida como um construto cultural em sua conexão com gênero/masculinidade, ainda pouco visualizada nos estudos da área da saúde. O referencial teórico-metodológico que orienta as análises situa-se nos campos dos estudos culturais, de gênero, da enfermagem e da sociologia da saúde. Os objetivos foram compreender as trajetórias identitárias de homens doentes renais crônicos e entender como o gênero constitui e marca essas trajetórias, assim como descrever e problematizar as estratégias que homens doentes renais crônicos desenvolvem para lidar com a doença e com a nova identidade que assumem. Desenvolveu-se um trabalho de campo, utilizando alguns procedimentos de investigação etnográfica. Por sete meses, um grupo de nove homens foi acompanhado durante suas sessões de tratamento substitutivo renal, a hemodiálise: nos primeiros três meses, através da observação participante de todo o contexto da unidade renal e, posteriormente, mediante entrevistas em profundidade com pacientes e suas cuidadoras domiciliares. Assim, foi constituído e organizado o material empírico que possibilitou as análises deste estudo. Tal movimento analítico possibilitou descrever e problematizar o processo saúde/doença e seus efeitos na vida desses homens: as alterações corporais, os medos da morte e de depender da máquina, os riscos e as incertezas do tratamento, as perdas no trabalho e a reconfiguração de suas masculinidades. Foi possível, também, descrever e analisar os suportes que organizam, cuidam e governam suas vidas durante o processo de tornarem-se doentes, bem como os processos através dos quais eles se (re)constroem como homens, em sua nova identidade de doente renal crônico, com formas de cuidados de si e reorganização de vida, trabalho, relações e apegos. Como resultados, identificou-se que tais pacientes demoram a tomar consciência desse processo: sofrem, questionam-se, brigam consigo mesmos, com as pessoas próximas e com a máquina. A possibilidade da morte passa a estar sempre presente, por isso reorganizam suas vidas em torno de objetivos pequenos, alcançáveis em menos tempo. Voltam-se, então, para a família e para a clínica em que fazem seu tratamento, mas com dificuldades de se adaptar a esses espaços que acreditam não lhes pertencer. E, muito lentamente, vão (re)construindo suas identidades. / This thesis discusses the identity re-constructions of men to become chronic kidney disease patients and their relations with care. The disease is perceived as a cultural construct in its connection with gender/masculinity, still not frequent in health studies. The theoretical and methodological framework that guides the analysis is situated in the fields of cultural, gender, nursing and health sociology studies. The objectives were to understand the identity trajectories of men with chronic renal failure patients and to understand how gender constitute and mark these pathways, as well as describing and problematizing strategies these men develop to cope with illness and with the new identity they assume. It was developed a field work, using some ethnographic research procedures. For seven months, a group of nine men was accompanied during their sessions of renal substitutive treatment, hemodialysis: in the first three months, through participant observation of the entire context of renal unit, and later through interviews with patients and their home caregivers. Thus, it was formed and organizes the empirical material which allowed the analysis in this study. That analytic movement enabled to describe and to question the health/illness process and its effects on these men‟s lives: body changes, fear of death and depending on the machinery, risks and doubts of treatment, work losses and masculinities reconfiguration. It was also possible to report and analyze the supports which organize, take care and govern their lives during the process of becoming sick, as well as the process through which they re-construct themselves as men, in their new chronic renal patient identity, and other forms of self care and reorganization of life, work, relations and passions. As results, it was found that such patients are slow to realize this process: they suffer, question themselves, fight themselves, with close people and with the machine. The possibility of death becomes always present, so they reorganize their lives around small goals, reachable in less time. Then they return to family and to the clinic where their treatment occurs, but struggling to adapt to these spaces in which they do not believe to belong. And, very slowly, they re-construct their identities. / Esta tesis trata sobre las re(construcciones) identitarias de hombres cuando adquieren la enfermedad renal crónica y sobre sus relaciones con el cuidado. La enfermedad se percibe como un constructo cultural en su conexión con género/masculinidad, todavía poco visualizada en los estudios del área de la salud. El referencial teórico-metodológico que orienta los análisis se sitúa en los campos de los estudios culturales, de género, de la enfermería y de la sociología de la salud. Los objetivos fueron comprender las trayectorias identitarias de hombres con enfermedad renal crónica y entender cómo el género constituye y marca esas trayectorias, así como describir y problematizar las estrategias que hombres con enfermedad renal crónica desarrollan para enfrentar la enfermedad y la nueva identidad que asumen. Se desarrolló un trabajo de campo, utilizando algunos procedimientos de investigación etnográfica. Por siete meses se acompañó a un grupo de nueve hombres durante sus sesiones de terapia de reemplazo renal, la hemodiálisis: en los primeros tres meses, a través de la observación participante de todo el contexto de la unidad renal y, posteriormente, mediante entrevistas en profundidad con pacientes y sus cuidadoras domiciliares. Así se constituyó y organizo el material empírico que permitió los análisis de ese estudio. Tal movimiento analítico permitió describir y problematizar el proceso de salud/enfermedad y sus efectos en la vida de esos hombres: las alteraciones corporales, los miedos a la muerte y a depender de una máquina, los riesgos e incertidumbres del tratamiento, las pérdidas en el trabajo y la reconfiguración de sus masculinidades. Fue posible, además, describir y analizar los soportes que organizan, cuidan y gobiernan sus vidas durante el proceso de ponerse enfermos, así como los procesos a través de los que ellos se (re)construyen como hombres, en su nueva identidad de persona con enfermedad renal crónica, con formas de cuidados de sí y reorganización de vida, trabajo, relaciones y apegos. Como resultados, se identificó que tales pacientes tardan a concienciarse de ese proceso: sufren, se cuestionan, pelean consigo mismos, con las personas cercanas y con la máquina. La posibilidad de la muerte pasa a estar siempre presente, por eso reorganizan sus vidas alrededor de objetivos pequeños, alcanzables en menos tiempo. Se vuelven entonces a la familia y a la clínica en la que hacen su tratamiento, pero con dificultades de adaptarse a esos espacios que creen que no les pertenece. Y muy lentamente van (re)construyendo sus identidades.