INTRODUÇÃO: O distúrbio mineral e ósseo (DMO) contribue significativamente para a redução da sobrevida em pacientes em terapia renal substibutiva (TRS). Os artigos que tratam do assunto, em sua grande maioria, envolvem pacientes submetidos a hemodiálise (HD) e essas publicações embasam as principais diretrizes (Kidney Disease Outcomes Quality Initiative - KDOQI - e o Kidney Disease: Improving Global Outcomes - KDIGO). MÉTODOS: Utilizamos a base de dados do Brazilian Peritoneal Dialysis (BRAZPD), estudo multicêntrico prospectivo, observacional, que avaliou pacientes em diálise peritoneal (DP), entre dezembro de 2004 e janeiro de 2011. Dos 9905 pacientes incluídos nessa base, selecionamos 844 que apresentavam dados demográficos, clínicos e laboratoriais completos e tempo em DP superior a 6 meses. Esse grupo de pacientes foi avaliado no seguimento de 24 meses. As variáveis de confusão foram corrigidas por modelos estatísticos (Cox e competing risk) e os níveis séricos de cálcio (Ca), fósforo (P) e paratormônio (PTH) relacionados com a sobrevida dos pacientes. RESULTADOS: Encontramos níveis menores de relative hazard quando os pacientes apresentavam valores de Ca e P próximos a 9,7 e 5,0 mg/dL, respectivamente. Encontramos significância estatística ao associar os níveis de Ca categorizados, conforme a orientação do KDIGO (Ca: 8,4 - 10,2 mg/dL, p = 0,03), e a sobrevida. Da mesma forma foi encontrada associação entre os níveis de P e a sobrevida dos pacientes, categorizados segundo as recomendações do KDOQI e KDIGO (P: 3,5 - 5,5 mg/dL, p < 0,01, para ambos). Outros limites de Ca (8,6 - 10,3 mg/dL, p < 0,01) e P (3,5 - 6,7 mg/dL, p < 0,01), encontrados nesse estudo, mostraram risco adicional. Apesar dos pacientes com níveis de PTH próximos a 532 pg/mL apresentarem menor relative hazard, não encontramos diferença significativamente estatística para sobrevida quando categorizados para valores de PTH tanto conforme o KDOQI (150 - 300 pg/mL) quanto para o KDIGO (150- 600 pg /mL). CONCLUSÕES: Em conclusão, manter os níveis de Ca conforme as orientações do KDIGO e P conforme orientações das duas diretrizes mostraram-se eficazes para melhora da sobrevida. Valores de Ca e P, propostos por esse estudo, evidenciaram risco adicional quando os valores ultrapassaram 8,6 - 10,3 mg/dL e 3,5 - 6,7 mg/dL, respectivamente. Os níveis de PTH não se associaram a sobrevida, mesmo quando dentro dos limites recomendados pelas duas diretrizes / INTRODUCTION: Mineral and bone disorders (MBD) contribute significantly to reduced survival of patients on dialysis. The main guidelines, Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO), related to the subject, were based upon the mostly in articles involving hemodialysis patients. The aim of our study was to analyze calcium (Ca), phosphorus (P) and parathyroid hormone (PTH) as predictors of survival in the Brazilian Peritoneal Dialysis II (BRAZPDII) cohort. METHODS: We used the Brazilian Peritoneal Dialysis II (BRAZPDII) database, an observational multi-centric prospective study, which assessed patients on Peritoneal Dialysis (PD) between December 2004 and January 2011. Amongst 9,905 patients included in this base, we selected 844 who presented complete demographic, clinical and laboratory data as well as 6 months on PD. This group of patients was followed up for 24 months. The confounding variables were included in multivariate models (Cox and competing risk), serum levels of Ca, P and PTH were the variables of interest and associated with patients\' survival on PD. RESULTS: Ca and P presenting improvements association with relative hazard when the values close to 9.7 and 5.0 mg/dL, respectively. We found a significant association between the levels of calcium, categorized by KDIGO (Ca: 8.4 - 10.2 mg/dL), and survival (p = 0.03), likewise, a compelling association between levels of P, categorized by both guidelines (KDOQI and KDIGO - P: 3.5 - 5.5 mg/dL, p < 0.01). Other ranges of Ca, (8.6 - 10.3 mg/dL, p < 0.01) and P (3.5 - 6.7 mg/dL, p < 0.01), which were proposed in this study, have shown additional risk. In spite of patients with PTH levels close to 532 pg/mL show better survival, we found no significant statistical association values of PTH categorized according to both guidelines, KDOQI (150 - 300 pg/mL) and KDIGO (150 - 600 pg/mL). CONCLUSION: In conclusion, the ranges levels of Ca proposed by KDIGO and P proposed by the both guidelines, and based in hemodialysis patients studies, has improved survival also in patients on PD. Higher levels of Ca and P have shown additional risk. Despite PTH being in the limits recommended in both guidelines, they were not associated with survival

Konventionelle hitzesterilisierte, glukosehaltige Peritonealdialyselösungen (PDL) sind aufgrund ihres niedrigen pH-Wertes, ihrer hohen Glukosekonzentration und Osmolalität und ihres Gehaltes an Glukosedegradationsprodukten (GDP) bioinkompatibel. Alternativen zu glukosehaltigen PDL stellen aminosäuren- oder icodextrinhaltige PDL dar. Daneben enthalten auch neuere Glukose-PDL in Doppelkammersystemen aufgrund der Sterilisation von Glukose bei sehr niedrigem pH nur noch sehr geringe GDP-Konzentrationen. In dieser Arbeit wurden die akuten und chronischen Wirkungen verschiedener PDL auf humane peritoneale Mesothelzellen (HPMC) untersucht. Konfluente HPMC wurden mit den zu testenden PDL (glukosehaltige hitze- versus filtersterilisierte und konventionelle versus Doppelkammer-Glukose-PDL, 1% Aminosäuren-PDL und Icodextrin - alle bei neutralem pH-Wert) akut (1-4 Stunden Präinkubation) bzw. chronisch (bis zu 10 Tage) inkubiert. Die Zellvitalität (MTT-Assay) und IL-1beta-stimulierte Sekretion von IL-6 (Zellfunktion) wurden untersucht. Die akute und chronische Exposition von HPMC gegenüber hitzesteriliserten Peritonealdialyselösungen führte zu einer signifkanten Reduktion von Vitalität und Funktion der Zellen. Demgegenüber führte die Inkubation mit filtersteriliserten PDL und GDP-armen PDL zu einer weniger starken Beeinflussung von Vitalität und Funktion. Die aminosäurenhaltige PDL beeinflusste weder akut noch chronisch die Vitalität bzw. Funktion der Zellen negativ. Hingegen unterschied sich die icodextrinhaltige Lösung nicht wesentlich von der hitzesteriliserten PDL mit hohem Glukoseanteil. Die Verringerung des Gehaltes an GDP in PDL mittels Filtersterilisation bzw. alternativer Sterilisation in Zweikammerbeuteln hat einen positiven Einfluss auf Vitalität und Funktion von HPMC in vitro. Der Ersatz des osmotischen Agenz hingegen bedeutet nicht zwansgläufig eine bessere Biokompatibilität. / Conventional heat-sterilized glucose-containing peritoneal dialysis fluids (PDF) are bioincompatible due to their acidic pH, high glucose concentration and resulting hyperosmolality, and the presence of glucose degradation products (GDP). Alternatives to these solutions are PDL containing amino acids or icodextrin as the osmotic agent. Furthermore, novel glucose-based PDF contain only trace amounts of GDPs due to the sterilisation of glucose at very low pH in a dual-chamber container system. The present study examines the acute and chronic effects of different PDL on human peritoneal mesothelial cells (HPMC). Confluent HPMC were exposed to the different test PDF (glucose containing heat- versus filter-sterilised PDF and conventional versus dual-chambered glucose PDF, 1% amino-acid PDF and icodextrin – all at neutral pH) in an acute (1-4 hours preincubation) and chronic (up to 10 days) cell culture model. Cell viability (MTT assay) and IL-1beta stimulated IL-6 (cell function) release were assessed. Acute and chronic exposure of HPMC to heat-sterilised PDF resulted in a significant reduction of viability and cell function. In contrast, the incubation of filter-sterilised PDF and dual chambered low GDP solution had only minor effects on cell viability and function. Neither viability nor cell function were negatively affected by the amino-acid PDF following acute and chronic exposure. However, incubation with icodextrin resulted in a similar degree of inhibition as compared to incubation with conventional heat-sterilised glucose PDF. In conclusion, removal of GDP from PDF either via filter-sterilisation or manufacture in dual chambered containers helps to conserve viability and function of HPMC in vitro. However, the replacement of the osmotic agent per se does not necessarily result in improved biocompatibility.

A falência de ultrafiltração (UFF) é uma causa importante de interrupção da diálise peritoneal (DP) enquanto terapia renal substitutiva. Além da inflamação crônica e aguda causadas à membrana peritoneal (MP) pelos produtos de degradação da glicose, produtos avançados da glicosilação, pH ácido das soluções e infecções, -bloqueadores (BB) também foram implicados na gênese da UFF. A vasoconstrição arteriolar esplâncnica é considerada a causa provável da UFF por BB. O nebivolol (NV), um bloqueador 1-adrenérgico altamente seletivo que, diferente de outros BB, possui efeito vasodilatador por aumento de óxido nítrico (NO) por ativar a via L-arginina-NO, foi testado em pacientes idosos com ICC e levou à redução na mortalidade. O objetivo desse estudo é analisar os efeitos do NV sobre a ultrafiltração (UF), MP e características do efluente em um modelo animal de DP, através do estudo de fenômenos envolvidos na degeneração da MP e UFF, como transição epitélio mesenquimal (EMT) e fibrose, além de parâmetros humorais e celulares de inflamação. 21 camundongos C57BL/6 fêmeas, não urêmicos, com 12 a 14 semanas, foram submetidos à colocação de cateter peritoneal. Após uma semana, foram divididos em 3 grupos de 7 animais: grupo controle (observação 30 dias), grupo SDP (2 mL/ dia de solução glicosada de diálise peritoneal a 4,25% através do cateter, por 30 dias) e grupo NV (além da infusão, receberam 8 mg/kg/dia de NV por gavagem, por 30 dias). Após 30 dias, comparou-se espessura submesotelial, volume de UF, velocidades de transporte de pequenos solutos, marcação submesotelial de pan-citoqueratina, para quantificar EMT, contagem de vasos, linfangiogênese diafragmática e concentração de IL-6 e IL-10 no efluente. A espessura da MP foi de 23,14 m no grupo controle, no grupo SDP foi de 102,4 m e no grupo NV, 29,04 m, com p<0,05. O volume de UF foi 1,94mL para o grupo controle, para o grupo SDP, 1,56 mL e, para o grupo NV, 2,05 mL, também com p<0,05. Houve menor EMT, menor angiogênese e tendência a transporte mais lento de solutos no grupo tratado, assim como menor concentração de IL-6 e proporções de populações de linfócitos semelhantes às do grupo controle. Concluímos que a droga impediu o desenvolvimento de UFF, através do bloqueio de fenômenos como EMT, espessamento da MP e neoangiogênese, além de preservar características de imunidade celular e humoral locais, merecendo ser estudada em pacientes submetidos à DP / Ultrafiltration failure (UFF) is a major cause of peritoneal dialysis (PD) discontinuation. Besides peritoneal membrane (PM) acute and chronic inflammation caused by glucose degradation products, advanced glycation end-products, acidic pH of the solutions and peritoneal infections, also -blockers (BBs) have been implicated in UFF genesis. Splanchnic arteriolar vasoconstriction has been considered the probable cause of UFF induced by BBs. Nebivolol (NV), a highly selective 1-adrenergic blocker, unlike other BBs, has a vasodilatory effect caused by its ability to increase nitric oxide (NO) through L-arginine-NO pathway activation. NV has been tested in elderly patients with congestive heart failure and led to mortality reduction. The aim of this work is to analyze the effects of NV over ultrafiltration (UF), PM and effluent characteristics in an animal model of PD. For that end, phenomena known to be involved in PM degeneration and UFF, such as epithelial-to-mesenchymal transition (EMT), fibrosis, as well as cellular and humoral parameters of inflammation have been studied. 21 C57BL/ 6 female non uremic mice, ageing 12 to 14 weeks, underwent peritoneal catheter placement. One week later, they were divided into 3 groups of 7 animals: control group (observation for 30 day), PDF group (2 mL/ day of 4.25% dextrose peritoneal dialysis fluid injected through the catheter for 30 days) and NV group (besides the PDF infusion, this group received 8 mg/ kg/ day of NV by gavage, for 30 days). After 30 days, submesotelial thickness, UF volume, small solute transport speed, submesotelial pan-cytokeratin staining (EMT quantification), vessel count, diaphragmatic lymphangiogenesis and IL-6 and IL-10 concentrations in the effluent were compared. PM thickness was 23.14 m in the control group, 102.4 m in the PDF group and 29.04 m in the NV group, p <0.05. UF volume was 1.94 mL in the control group, 1.56 mL in the SDP group, and in the NV group, 2.05 mL, p <0.05. There was less EMT, less angiogenesis and a tendency to a slower solute transport in the treated group. Lower levels of IL-6 and similar lymphocyte populations proportions to the control group were also found. We conclude that the drug can prevent UFF development, through blockade of phenomena such as EMT, PM thickening and neoangiogenesis, while characteristics of local cellular and humoral immunity were preserved. These results warrant a clinical study of the drug in PD patients

Chan Fat-Yiu. / Thesis (M.Sc.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 85-93). / Abstracts in English and Chinese. / ACKNOWLEDGEMENTS --- p.4 / SUMMARY --- p.5 / ABBREVIATIONS --- p.9 / LIST OF TABLES --- p.11 / LIST OF FIGURES --- p.13 / Chapter CHAPTER I --- INTRODUCTION --- p.14 / Chapter 1.1 --- The Historical Aspects of C-Reaction Protein --- p.15 / Chapter 1.2 --- Biochemistry of CRP --- p.16 / Chapter 1.3 --- Physiology of CRP --- p.18 / Chapter 1.4 --- Current Clinical Applications of Serum CRP Assay --- p.19 / Chapter 1.5 --- Recent Findings of CRP --- p.21 / Chapter 1.5.1 --- Pathophysiology of atherosclerosis --- p.22 / Chapter 1.5.2 --- A nother atherogenic risk factor: hs- CRP --- p.26 / Chapter 1.5.3 --- Can hs-CRP replace other risk factors? --- p.30 / Chapter 1.5.4 --- Altering hs-CRP result in medication --- p.32 / Chapter 1.6 --- Methods of Measurement of CRP Concentration --- p.33 / Chapter 1.7 --- Analytical Considerations in the Measurement of hs-CRP --- p.34 / Chapter CHAPTER II --- OBJECTIVES AND SIGNIFICANCE --- p.36 / Chapter 2.1 --- Objectives --- p.37 / Chapter 2.2 --- Issues and Problems --- p.37 / Chapter 2.3 --- Significance and Value of this Study --- p.38 / Chapter CHAPTER III --- MA TERIALS AND METHODS I Setting up the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.39 / Chapter 3.1 --- Materials --- p.40 / Chapter 3.1.1 --- Reagents from Roche Diagnostics --- p.40 / Chapter 3.1.2 --- Reagents for the Beckman Coulter Array ® Analyzer --- p.40 / Chapter 3.1.3 --- In-house reagents --- p.41 / Chapter 3.2. --- Apparatus and Equipment --- p.41 / Chapter 3.2.1 --- Hitachi 911 Analyzer --- p.41 / Chapter 3.2.2 --- Beckman Coulter Array ® 360 Analyzer --- p.42 / Chapter 3.3 --- The Tina-quant a C-Reactive Protein (Latex) Ultrasensitive Assay --- p.42 / Chapter 3.3.1 --- Priniciple of the Dual-Radius Enhanced Latex (DuREL´ёØ) technology --- p.42 / Chapter 3.3.2 --- Assessment of Analytical Performance --- p.45 / Chapter CHAPTER IV --- MA TERIALS AND METHODS II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.48 / Chapter 4.1 --- Patient Recruitment --- p.49 / Chapter 4.2. --- Blood Specimens --- p.49 / Chapter 4.3 --- Assay Methods --- p.50 / Chapter 4.3.1 --- hs-CRP --- p.50 / Chapter 4.3.2 --- TC --- p.50 / Chapter 4.3.3 --- TG --- p.51 / Chapter 4.3.4 --- HDL-C --- p.51 / Chapter 4.3.5 --- LDL-C --- p.52 / Chapter 4.3.6 --- Apo A-1 --- p.52 / Chapter 4.3.7 --- Apo B --- p.53 / Chapter 4.3.8 --- Lp(a) --- p.53 / Chapter 4.4 --- Ultrasound measurement of carotid artery inter-media thickness --- p.53 / Chapter 4.5 --- Statistical analysis --- p.54 / Chapter CHAPTER V --- RESUTLSI Setting up the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.55 / Chapter 5.1 --- Imprecision --- p.56 / Chapter 5.2 --- Linearity --- p.56 / Chapter 5.3 --- Recovery --- p.56 / Chapter 5.4 --- Detection Limit --- p.57 / Chapter 5.5 --- Carry-over --- p.57 / Chapter CHAPTER VI --- RESULTS II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.63 / Chapter 6.1 --- Patient Recruitment --- p.64 / Chapter 6.2 --- Chinese chronic-renal-failure patients with AVD --- p.64 / Chapter 6.3 --- Chinese chronic-renal-failure patients with CVC --- p.65 / Chapter CHAPTER VII --- DISCUSSION I Performance of the serum hs-CRP assay on the Hitachi 911 Analyzer --- p.75 / Chapter 7.1 --- "Imprecision, Detection Limit, Linearity, and Recovery of hs-CRP Assay" --- p.76 / Chapter 7.1.1 --- Imprecision --- p.76 / Chapter 7.1.2 --- Detection Limit --- p.76 / Chapter 7.1.3 --- Linearity --- p.76 / Chapter 7.1.4 --- Recovery --- p.77 / Chapter 7.2 --- Overall Performance --- p.77 / Chapter CHAPTER VIII --- DISCUSSION II Serum hs-CRP in Chinese chronic-renal-failure patients with atherosclerotic vascular disease or cardiac valve calcification --- p.79 / Chapter 8.1 --- CAPD Patients --- p.80 / Chapter 8.2 --- Serum hs-CRP Concentration of AVD and CVC Patients --- p.81 / Chapter 8.3 --- Other risk factors in AVD and CVC Patients --- p.82 / Chapter 8.4 --- Conclusion --- p.83 / REFERENCES --- p.85

Peritoneal dialysis (PD) is a form of renal replacement therapy using the peritoneum as a dialysis membrane. PD solutions employed to remove nitrogen metabolites and excess plasma fluid, and to restore electrolyte and acid-base balance are being developed to minimize local and systemic inflammatory responses while maintaining peritoneal homeostasis and host defense. The effect of chronic action of PD solutions on the peritoneum results in its remodeling and, possibly, eventual loss of peritoneal ultrafiltration capacity. Factors most responsible for late complications and peritoneal remodeling include high glucose levels in PD solutions, and the presence and formation of glucose degradation products (GDP) and advanced glycation end - products (AGEs) in the peritoneal cavity. The aim of our study described in this dissertation was to test various PD solutions with different glucose content and GDP and, using AGEs receptor ligands, to define their systemic effects and identify PD solutions with highest biocompatibility. This part of the dissertation characterizes conventional glucose - based solutions, low - glucose and GDP load solutions as well as glucose polymer (icodextrin) - based PD solutions while determining the plasma and dialysate levels of soluble receptor for AGEs (s - RAGE) and its...

A falência de ultrafiltração (UFF) é uma causa importante de interrupção da diálise peritoneal (DP) enquanto terapia renal substitutiva. Além da inflamação crônica e aguda causadas à membrana peritoneal (MP) pelos produtos de degradação da glicose, produtos avançados da glicosilação, pH ácido das soluções e infecções, -bloqueadores (BB) também foram implicados na gênese da UFF. A vasoconstrição arteriolar esplâncnica é considerada a causa provável da UFF por BB. O nebivolol (NV), um bloqueador 1-adrenérgico altamente seletivo que, diferente de outros BB, possui efeito vasodilatador por aumento de óxido nítrico (NO) por ativar a via L-arginina-NO, foi testado em pacientes idosos com ICC e levou à redução na mortalidade. O objetivo desse estudo é analisar os efeitos do NV sobre a ultrafiltração (UF), MP e características do efluente em um modelo animal de DP, através do estudo de fenômenos envolvidos na degeneração da MP e UFF, como transição epitélio mesenquimal (EMT) e fibrose, além de parâmetros humorais e celulares de inflamação. 21 camundongos C57BL/6 fêmeas, não urêmicos, com 12 a 14 semanas, foram submetidos à colocação de cateter peritoneal. Após uma semana, foram divididos em 3 grupos de 7 animais: grupo controle (observação 30 dias), grupo SDP (2 mL/ dia de solução glicosada de diálise peritoneal a 4,25% através do cateter, por 30 dias) e grupo NV (além da infusão, receberam 8 mg/kg/dia de NV por gavagem, por 30 dias). Após 30 dias, comparou-se espessura submesotelial, volume de UF, velocidades de transporte de pequenos solutos, marcação submesotelial de pan-citoqueratina, para quantificar EMT, contagem de vasos, linfangiogênese diafragmática e concentração de IL-6 e IL-10 no efluente. A espessura da MP foi de 23,14 m no grupo controle, no grupo SDP foi de 102,4 m e no grupo NV, 29,04 m, com p<0,05. O volume de UF foi 1,94mL para o grupo controle, para o grupo SDP, 1,56 mL e, para o grupo NV, 2,05 mL, também com p<0,05. Houve menor EMT, menor angiogênese e tendência a transporte mais lento de solutos no grupo tratado, assim como menor concentração de IL-6 e proporções de populações de linfócitos semelhantes às do grupo controle. Concluímos que a droga impediu o desenvolvimento de UFF, através do bloqueio de fenômenos como EMT, espessamento da MP e neoangiogênese, além de preservar características de imunidade celular e humoral locais, merecendo ser estudada em pacientes submetidos à DP / Ultrafiltration failure (UFF) is a major cause of peritoneal dialysis (PD) discontinuation. Besides peritoneal membrane (PM) acute and chronic inflammation caused by glucose degradation products, advanced glycation end-products, acidic pH of the solutions and peritoneal infections, also -blockers (BBs) have been implicated in UFF genesis. Splanchnic arteriolar vasoconstriction has been considered the probable cause of UFF induced by BBs. Nebivolol (NV), a highly selective 1-adrenergic blocker, unlike other BBs, has a vasodilatory effect caused by its ability to increase nitric oxide (NO) through L-arginine-NO pathway activation. NV has been tested in elderly patients with congestive heart failure and led to mortality reduction. The aim of this work is to analyze the effects of NV over ultrafiltration (UF), PM and effluent characteristics in an animal model of PD. For that end, phenomena known to be involved in PM degeneration and UFF, such as epithelial-to-mesenchymal transition (EMT), fibrosis, as well as cellular and humoral parameters of inflammation have been studied. 21 C57BL/ 6 female non uremic mice, ageing 12 to 14 weeks, underwent peritoneal catheter placement. One week later, they were divided into 3 groups of 7 animals: control group (observation for 30 day), PDF group (2 mL/ day of 4.25% dextrose peritoneal dialysis fluid injected through the catheter for 30 days) and NV group (besides the PDF infusion, this group received 8 mg/ kg/ day of NV by gavage, for 30 days). After 30 days, submesotelial thickness, UF volume, small solute transport speed, submesotelial pan-cytokeratin staining (EMT quantification), vessel count, diaphragmatic lymphangiogenesis and IL-6 and IL-10 concentrations in the effluent were compared. PM thickness was 23.14 m in the control group, 102.4 m in the PDF group and 29.04 m in the NV group, p <0.05. UF volume was 1.94 mL in the control group, 1.56 mL in the SDP group, and in the NV group, 2.05 mL, p <0.05. There was less EMT, less angiogenesis and a tendency to a slower solute transport in the treated group. Lower levels of IL-6 and similar lymphocyte populations proportions to the control group were also found. We conclude that the drug can prevent UFF development, through blockade of phenomena such as EMT, PM thickening and neoangiogenesis, while characteristics of local cellular and humoral immunity were preserved. These results warrant a clinical study of the drug in PD patients

A modificação oxidativa da LDL possui um papel crucial na patogênese da aterosclerose que é uma das principais causas de mortalidade nos pacientes renais crônicos. Uma subfração de LDL modificada in vivo, denominada LDL eletronegativa (LDL-), é formada a partir de modificações da parte protéica (ApoB100) e lipídica (fosfolípides, triglicérides e colesterol) da LDL induzidas por diversos mecanismos. A LDL (-) tem menor afinidade pelos receptores da LDL, é citotóxica para células endoteliais e apresenta atividade pró-inflamatória, quando comparada à LDL nativa. Com o objetivo de investigar as alterações do estado nutricional relacionadas à formação da LDL(-) nos pacientes renais crônicos, analisou-se neste estudo as concentrações plasmáticas de LDL(-), anticorpos IgG anti-LDL(-) e seus imunocomplexos em pacientes sob hemodiálise (HD, n=25) ou sob diálise peritoneal (DP, n=11) e indivíduos saudáveis (grupo controle, n=10), relacionando-as ao perfil lipídico e às concentrações plasmáticas de &#945;-tocoferol e ascorbato. Os resultados mostraram que a concentração de LDL(-) foi maior (p&#60;0.01) nos pacientes hemodialisados (575,6&#177;233,1&#181;g/mL) quando comparados aos pacientes submetidos à diálise peritoneal (223,4&#177;117,5 &#181;g/mL) e aos controles (54,9&#177;33,3&#181;g/mL). Os níveis de anticorpos IgG anti-LDL(-) foram mais elevados (p&#60;0,00001) nos controles (O,36&#177;0,09&#181;g/mL), quando comparados aos pacientes DP (0,28&#177;0,12&#181;g/mL) e HD (0,2&#177;0,1 &#181;g/mL). As concentrações dos imunocomplexos no grupo controle (0,35&#177;0,20&#181;g/mL) foram significativamente maiores comparadas às dos grupos HD (0,15&#177;0,07&#181;g/mL) e DP (0,22&#177;0,07&#181;g/mL). Não houve diferença das concentrações plasmáticas de ascorbato e de alfa-tocoferol (normalizada pela concentração de colesterol) nos grupos estudados. A maioria da população estudada estava eutrófica, segundo o índice de massa corpórea (IMG). Conclui-se que as concentração de LDL(-) nos pacientes HD e DP foram significativamente mais elevadas, enquanto os níveis de anticorpos IgG anti-LDL(-) foram menores, nos pacientes HD e DP comparados ao grupo controle. As análises de correlação demonstraram que os valores de prega cutânea tricipital (PCT) se correlacionaram diretamente com as concentrações plasmáticas dos imunocomlexos (r= 0,37; p= 0,01) e inversamente com as concentrações plasmáticas de LDL(-) (r= - 0.37; p= 0,018). As concentrações plasmáticas dos anticorpos anti-LDL(-) se correlacionaram diretamente com os valores do IMC (r= 0,83 p=0,00001) e da circunferência da cintura (r= 0,75 p= 0,0001). / A minimally modified form of LDL, with structural ApoB100 modification and lower affinity by LDL receptors, has been described in blood plasma. This circulating modified form of LDL, named electronegative LDL, LDL(-), has increased negative charge, higher cytotoxicity and pro-inflammatory activity as compared to the native LDL. This LDL-is poorly described in hemodialysis and there is no study in peritoneal dialysis patients. Thus, the purpose of this study was to evaluate the relation of the nutritional status with the amount of electronegative LDL (LDL-), its autoantibodies and immune complexes (IC) in dialysed patients. LDL(-), its autoantibodies and IC were determined by ELISA in chronic kidney disease (CKD) patients undergoing hemodialysis (HD) or peritoneal dialysis (PD) and compared to subjects without CKD (controls). Nutritional status, lipid profile and plasma concentrations of alpha-tocopherol, ascorbate and immune complexes (IC) were also evaluated. Results are expressed as median of LDL-(&#181;g/mL) and anti-LDL(-) IgG (OD405 nm). The concentrations of LDL(-) were higher in HD patients (575.6&#177;233.1 &#181;g/mL) as compared to PD (223.4&#177;117.5&#181;g/mL) and control groups (54.9&#177;33.3&#181;g/mL) (p&#60;0.01). The anti-LDL(-) IgG auto-antibodies were elevated in controls (0.36&#177;0.09&#181;g/mL) in relation to PD patients (0.28&#177;0.12&#181;g/mL) and HD patients (0.2&#177;0.1 &#181;g/mL) , (p&#60;0.00001). A negative correlation was observed between anti¬-LDL(-)lgG and LDL(-) levels (r = -0.43; P = 0.003) in the studied groups. The concentrations of le in the control group (0.35&#177;0.20&#181;g/mL) were higher compared with HD (0.15&#177;0.07&#181;g/mL) and PD (0.22&#177;0.07&#181;g/mL) groups. No differences were found for the plasma levels of ascorbate and alpha-tocopherol (normalized by cholesterol concentration) among the studied groups The body mass index (BMI) was normal in the majority of the studied subjects. The highest LDL(-) concentrations were found in HD patients, and for the first time, we showed that PD patients also have high levels of LDL(-) when compared with non-CKD subjects. The levels of anti-LDL(-) IgG in CKD patients were lower compared to controls. The correlation analysis showed that the values for triceps skin fold were positively correlated with blood plasma concentrations of IC (r= 0.37; p=0.01) and negatively correlated with LDL(-) concentrations (r= - 0.37; P 0.018). The concentrations of anti-LDL(-) autoantibodies were directly ·correlated with BMI (r= 0.83 p=0.00001) and waist circunference (r= 0.75 p= 0.0001).

Afin de mieux connaitre puis d'optimiser les trajectoires suivies par les patients arrivés au stade terminal de leur insuffisance rénale chronique, il a été nécessaire de mettre au point des outils permettant de modéliser ces trajectoires complexes. Les différentes modalités de traitement n'ont pas été comparées une à une mais une approche globale a été privilégiée tenant compte d'une vision intégrée où les modalités de traitement sont considérées comme complémentaires et non concurrentielles. Ce travail de modélisation a utilisé des modèles à compartiments avec prise en compte de risque concurrents et un modèle de mélange pour données de survie avec fraction non à risque. Les paramètres des modèles ont été estimés à partir des données du registre du Réseau Épidémiologie et Information en Néphrologie (REIN). L'outil de prédiction développé a également pu être alimenté par les données de remboursement de l'assurance maladie (SNIIRAM) sur l'année 2009. Cette première version de l'outil a permis d'évaluer les conséquences en termes d'espérance de vie restreinte à 15 ans et de coût moyen par mois de différentes stratégies simulées de prise en charge des patients en IRCT dans le cadre d'une analyse médico-économique, en partenariat avec la Haute Autorité de Santé. L'objectif final de ce travail sera de proposer des outils d'aide à la décision reposant sur des stratégies de prise en charge les mieux adaptées aux besoins des patients. A terme, les outils développés lors de ce travail pourraient également servir de base à une plateforme de simulation afin d'accompagner les décideurs publics lors de la réflexion sur les schémas d'organisation sanitaire / In order to better understand and then optimize the trajectories followed by end-stage renal disease patients, it was necessary to develop tools to model these complex trajectories. The different treatment modalities were not compared but a comprehensive approach was preferred taking into account an integrated vision where treatment modalities are considered complementary and non-competitive. We used compartments models which took into account competitive risk and a mixture model for survival with fraction not at risk. The model parameters were estimated from the data from the Renal Epidemiology and Information Network registry. Reimbursement data from the national health insurance (SNIIRAM) were also used. The prediction tool developed was used to evaluate the consequences in terms of expected 15- years restricted lifetime and average cost per month for different strategies in a medicoeconomic analysis, in partnership with the Haute Autorité de Santé. The final aim of this work is to offer decision support tools based on strategies best adapted to patients’ needs. The tools developed in this work could also serve as a basis for a simulation platform to accompany public decision-makers in their reflection on health organization

Peritoneal dialysis (PD) is a form of renal replacement therapy using the peritoneum as a dialysis membrane. PD solutions employed to remove nitrogen metabolites and excess plasma fluid, and to restore electrolyte and acid-base balance are being developed to minimize local and systemic inflammatory responses while maintaining peritoneal homeostasis and host defense. The effect of chronic action of PD solutions on the peritoneum results in its remodeling and, possibly, eventual loss of peritoneal ultrafiltration capacity. Factors most responsible for late complications and peritoneal remodeling include high glucose levels in PD solutions, and the presence and formation of glucose degradation products (GDP) and advanced glycation end - products (AGEs) in the peritoneal cavity. The aim of our study described in this dissertation was to test various PD solutions with different glucose content and GDP and, using AGEs receptor ligands, to define their systemic effects and identify PD solutions with highest biocompatibility. This part of the dissertation characterizes conventional glucose - based solutions, low - glucose and GDP load solutions as well as glucose polymer (icodextrin) - based PD solutions while determining the plasma and dialysate levels of soluble receptor for AGEs (s - RAGE) and its...

La dialyse péritonéale (DP) est une thérapie d’épuration extra-rénale qui peut se réaliser à domicile par l’entremise d’une technologie. Elle exige, du patient certaines aptitudes, (motivation et compétence) et de l’équipe de soins, une organisation particulière pour arriver à une autonomie d’exécution de l’épuration. Dans un contexte de thérapie à domicile, comme celui de la dialyse péritonéale, le niveau d’autonomie des patients ainsi que les facteurs qui y sont associés n’ont pas été examinés auparavant. C’est l’objet de cette thèse. En se fondant sur la théorie de l’autodétermination et sur une revue de la littérature, un cadre conceptuel a été développé et fait l’hypothèse que trois types de facteurs essentiels pourraient influencer l’autonomie. Il s’agit de facteurs individuels, technologiques et organisationnels. Pour tester ces hypothèses, un devis mixte séquentiel, composé de deux volets, a été réalisé. Un premier volet qualitatif - opérationnalisé par des entrevues auprès de 12 patients et de 11 infirmières - a permis, d’une part, d’explorer et de mieux définir les dimensions de l’autonomie pertinente dans le cadre de la DP; d’autre part de bonifier le développement d’un questionnaire. Après validation, ce dernier a servi à la collecte de données lors du deuxième volet quantitatif et alors a permis d’obtenir des résultats auprès d’un échantillon probabiliste (n =98), tiré de la population des dialysés péritonéaux du Québec (N=700). L’objectif de ce deuxième volet était de mesurer le degré d’autonomie des patients, d’examiner les associations entre les facteurs technologiques, organisationnels ainsi qu’individuels et les différentes dimensions de l’autonomie. Des analyses univariées et multivariées ont été réalisées à cet effet. Les résultats obtenus montrent que quatre dimensions d’autonomie sont essentielles à atteindre en dialyse à domicile. Il s’agit de l’autonomie, sur le plan clinique, technique, fonctionnel (liberté journalière) et organisationnel (indépendance par rapport à l’institution de soins). Pour ces quatre types d’autonomie, les patients ont rapporté être hautement autonomes, un résultat qui se reflète dans les scores obtenus sur une échelle de 1 à 5 : l’autonomie clinique (4,1), l’autonomie technique (4,8), l’autonomie fonctionnelle (4,1) et l’autonomie organisationnelle (4,5). Chacun de ces types d’autonomie est associé à des degrés variables aux trois facteurs du modèle conceptuel : facteurs individuels (motivation et compétence), technologique (convivialité) et organisationnels (soutien clinique, technique et familial). Plus spécifiquement, la motivation serait associée à l’autonomie fonctionnelle. La convivialité serait associée à l’autonomie clinique, alors que la myopathie pourrait la compromettre. La convivialité de la technologie et la compétence du patient contribueraient à une meilleure autonomie organisationnelle. Quant à l’autonomie sur le plan technique, tous les patients ont rapporté être hautement autonomes en ce qui concerne la manipulation de la technologie. Ce résultat s’expliquerait par une formation adéquate mise à la disposition des patients en prédialyse, par le suivi continu et par la manipulation quotidienne pendant des années d’utilisation. Bien que dans cette thèse la technologie d’application soit la dialyse péritonéale, nous retenons que lorsqu’on transfère la maîtrise d’une technologie thérapeutique à domicile pour traiter une maladie chronique, il est primordial d’organiser ce transfert de telle façon que les trois facteurs techniques (convivialité), individuels (motivation, formation et compétence), et organisationnels (soutien de l’aidant) soient mis en place pour garantir une autonomie aux quatre niveaux, technique, clinique, fonctionnel et organisationnel. / Peritoneal dialysis (PD) is a home-based therapy that purifies blood via a peritoneal membrane to treat patients with end-stage renal disease. It requires from the patient some aptitudes (competence and motivation) and from the caregivers a particular organization to foster patient autonomy. However, in the context of a home-based therapy, such as in peritoneal dialysis, autonomy is a poorly conceptualized entity and has not been specifically measured. The objective of this thesis was to identify the dimensions and the levels of the patient’s autonomy and the factors associated in the context of using peritoneal dialysis. On the basis of the Self-determination theory and a literature review, a conceptual framework was developed which assumed that three main factors could influence the autonomy: individual (motivation, competence), technological (user-friendliness), and organizational factors (different types of support). To test the assumptions supported by our framework, a mixed method design composed of two sequential phases was developed. A first qualitative phase - conducted through open-ended interviews with 12 patients and 11 nurses - was performed to explore and better define the dimensions of autonomy of the patients treated by peritoneal dialysis. The data obtained was used to enhance the development of a questionnaire, which was mailed during the second quantitative phase to a random sample of patients. This questionnaire was completed and returned by 98 patients from the population of Québec peritoneal dialysis users (N=700). The objective of this second phase was to assess the patients’ autonomy levels and to examine the relationship between the three factors (individual, technological and organizational) and the four dimensions of autonomy. Data were analysed using univariate statistics and multiple linear regression model. Our results show that four dimensions of autonomy are essential to achieve peritoneal dialysis at home : clinical autonomy (performing basic clinical tasks), technical (technical tasks), functional (daily freedom) and organizational autonomy (independence from the care centre). The patients gave higher rating for organizational autonomy (4,5 mean score on five-point Likert scale); 4,1 for clinical autonomy; 4,1 score for functional autonomy and 4,8 for technical autonomy. Each of these dimensions of autonomy was associated with one or more of three factors from the conceptual model : individual, technology and organizational factors. In some cases, the type of the peritoneal dialysis technology (manual or automated) contributed to some dimension of autonomy. More specifically, the motivation could facilitate functional autonomy. The technology user-friendliness might allow greater clinical autonomy, but a muscular disease could compromise it. The patient competence and the user-friendliness might contribute to the organizational autonomy. Finally, all the patients reported being highly autonomous on manipulating the technology. This result could be explained by adequate training during the predialysis period, continuous support and daily manipulation of the technology. Even though our results were obtained for the peritoneal dialysis application, we retain that when transferring the handling of a home therapy technology to treat a chronic disease, it is essential to coordinate the transfer so that the three factors, the user-friendliness, individual factors such as motivation and competence, and organizational factors (different types of support) are in place to ensure autonomy at the four levels, technical, clinical, functional and organizational.