Diabetic nephropathy is the main cause for initiation of renal replacement therapy and early symptoms in patients include increased glomerular filtration rate (GFR), decreased oxygen tension and albuminuria, followed by a progressive decline in GFR and loss of kidney function. Experimental models of diabetes display increased GFR, decreased tissue oxygenation and nitric oxide bioavailability. These findings are likely to be intertwined in a mechanistic pathway to kidney damage and this thesis investigated their roles in the development of diabetic nephropathy. In vivo, diabetes-induced oxidative stress stimulates renal tubular Na+ transport and in vitro, proximal tubular cells from diabetic rats display increased transport-dependent oxygen consumption, demonstrating mechanisms contributing to decreased kidney oxygenation. In control animals, endogenous adenosine reduces vascular resistance of the efferent arteriole via adenosine A2-receptors resulting in reduced filtration fraction. However, in diabetes, adenosine A2-signalling is dysfunctional resulting in increased GFR via increased filtration fraction. This is caused by reduced adenosine A2a receptor-mediated vasodilation of efferent arterioles. The lack of adenosine-signaling in diabetes is likely due to reduced local adenosine concentration since adenosine A2a receptor activation reduced GFR only in diabetic animals by efferent arteriolar vasodilation. Furthermore, sub-optimal insulin treatment also alleviates increased filtration pressure in diabetes. However, this does not affect GFR due to a simultaneously induction of renal-blood flow dependent regulation of GFR by increasing the filtration coefficient. In diabetes, there is decreased bioavailability of nitric oxide, resulting in alterations that may contribute to diabetes-induced hyperfiltration and decreased oxygenation. Interestingly, increased plasma concentration of l-arginine, the substrate for nitric oxide production, prevents the development of increased GFR and proteinuria, but not increased oxygen consumption leading to sustained intra-renal hypoxia in diabetes. This thesis concludes that antioxidant treatment directed towards the NADPH oxidase as well maneuvers to promote nitric oxide production is beneficial in diabetic kidneys but is targeting different pathways i.e. transport-dependent oxygen consumption in the proximal tubule by NADPH oxidase inhibition and intra-renal hemodynamics after increased plasma l-arginine. Also, the involvement and importance of efferent arteriolar resistance in the development of diabetes-induced hyperfiltration via reduced adenosine A2a signaling is highlighted.

Patients with chronic kidney disease are at higher risk of developing cardiovascular disease. The complex, interaction between the kidney and the cardiovascular system is incompletely understood, particularly at the early stages of the cardiovascular continuum. The overall aim of this thesis was to clarify novel aspects of the interplay between the kidney and the cardiovascular system at different stages of the cardiovascular continuum; from risk factors such as insulin resistance, inflammation and oxidative stress, via sub-clinical cardiovascular damage such as endothelial dysfunction and left ventricular dysfunction, to overt cardiovascular death. This thesis is based on two community-based cohorts of elderly, Uppsala Longitudinal Study of Adult Men (ULSAM) and Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS). The first study, show that higher insulin sensitivity, measured with euglycemic-hyperinsulinemic clamp technique was associated to improve estimated glomerular filtration rate (eGFR) in participants with normal fasting plasma glucose, normal glucose tolerance and normal eGFR. In longitudinal analyses, higher insulin sensitivity at baseline was associated with lower risk of impaired renal function during follow-up. In the second study, eGFR was inversely associated with different inflammatory markers (C-reactive protein, interleukin-6, serum amyloid A) and positively associated with a marker of oxidative stress (urinary F2-isoprostanes). In line with this, the urinary albumin/creatinine ratio was positively associated with these inflammatory markers, and negatively associated with oxidative stress. In study three, higher eGFR was associated with better endothelial function as assessed by the invasive forearm model. Further, in study four, higher eGFR was significantly associated with higher left ventricular systolic function (ejection fraction). The 5th study of the thesis shows that higher urinary albumin excretion rate (UAER) and lower eGFR was independently associated with an increased risk for cardiovascular mortality. Analyses of global model fit, discrimination, calibration, and reclassification suggest that UAER and eGFR add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent cardiovascular disease. Conclusion: this thesis show that the interaction between the kidney and the cardiovascular system plays an important role in the development of cardiovascular disease and that this interplay begins at an early asymptomatic stage of the disease process.

No description available.

No description available.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Die Mehrheit chronischer Nierenerkrankungen wird durch glomeruläre Defekte hervorgerufen. In dieser Arbeit wurde deshalb im Mausmodell die Bedeutung der Kollagenrezeptoren DDR1 (Discoidin Domain Rezeptor 1) und ITGA2 (Integrin Alpha 2) in der Pathogenese von glomerulären Nierenerkrankungen untersucht. Von zentralem Interesse waren neben der Betrachtung des renalen Phänotyps, die Analyse der glomerulären Basalmembran sowie die Prüfung auf Vorhandensein nierenschädigender Faktoren. Zur Orientierung angefertigte H.E.-Färbungen waren lichtmikroskopisch unauffällig, jedoch ließ sich mittels Gelelektrophorese eine Mikro-, Makro- und Albuminurie mit einem Maximum zum Zeitpunkt von 100 Lebenstagen nachweisen, die mit 200 Tagen wieder stark sank. Auf dem Boden der nierenschädigenden Proteinurie, zeigten die Western-Blot-Analysen das Vorhandensein der Zytokine TGF-ß und CTGF auf. Die zur Detektion von Narbengewebe durchgeführte Fibronektinfärbung, erbrachte keinerlei weiterführende Anhaltspunkte. In der Elektronenmikroskopie ließ sich vereinzelt eine Mehrschichtung der GBM nachweisen, was als Ausreifungsstörung interpretiert wurde. Der Wegfall der beiden Kollagenrezeptoren ITGA2 und DDR1 scheint somit die Interaktion der Podozyten mit der GBM zu stören. Dies hat eine Proteinurie zur Folge. In Folge dessen werden profibrotische Zytokine sezerniert. Das Fehlen der beiden Kollagenrezeptoren DDR1 und ITGA2 führte jedoch nicht zur Ausbildung einer renalen Fibrose, wie in der Fibronektin-Färbung gezeigt werden konnte. Gross und Girgert zeigten, dass nierenkranke Mäuse nach dem Verlust von DDR1 oder ITGA2 einen verzögerten Verlauf der Nierenfibrose entwickelten. Vielversprechend scheinen Untersuchungen z.B. am Mausmodell Col4A3/DDR1/ITGA2 -/- oder an einer diabetischen ITGA2/DDR1 -/- Maus. Gesetzt dem Fall, dass eine renale Fibrose im Vergleich zum Einzelknockout noch später eintritt, eignen sich diese beiden Kollagenrezeptoren als therapeutisches Ziel. Aktuell stehen nur wenige nephroprotektive Medikamente, wie ACE-Hemmer, zur Verfügung. Anti-Integrine und Inhibitoren gegen Tyrosinkinase-Rezeptoren, wie DDR1, haben bereits Einzug in den klinischen Alltag gehalten und stellen eventuell einen wirksamen Ansatzpunkt zur Verhinderung einer renalen Fibrose dar.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

A Doença da Artéria Periférica (DAP) é o resultado do processo aterosclerótico das artérias dos membros superiores, inferiores, aorta abdominal e seus ramos viscerais. Nosso objetivo foi detectar a DAP correlacionando-a com fatores de risco (FR) e a filtração glomerular estimada (FGe) nos pacientes com ≥30 anos, assistidos na Unidade docente - assistencial de Angiologia (UDA) do Hospital Universitário Pedro Ernesto da Faculdade de Ciências Médicas - UERJ, com o intuito de descrever os FR e associação com doença renal crônica à DAP, a partir da aferição do índice tornozelo-braço (ITB); determinar a alteração da FGe por equações, relacionando-a à progressão da DAP. Foi usado um questionário padrão e o ITB para identificar os pacientes com e sem DAP. Correlacionou-se as variáveis laboratoriais, como os níveis séricos de colesterol, triglicerídeos, HDL-c, LDL-c, glicemia, homocisteína com a FGe e com o ITB. As análises estatísticas foram feitas pelo programa Statistical Package for the Social Sciences (SPSS) 16.0 Os resultados apontaram para a importância do ITB no diagnóstico da DAP, com configuração de graus de obstrução leve, discreta, moderada e grave para os sintomáticos, e a identificação dos assintomáticos, possibilitando intervenção nos fatores de risco demarcados e o controle de suas complicações. O tabagismo mostou-se como o FR com razão de risco mais importante para DAP. A hipertensão sistólica e a diastólica foram variáveis clínicas mais significativas que o diabetes mellitus. Os marcadores séricos tradicionais para DAP: colesterol total, triglicerídeos e glicemia mostraram significância estatística. A homocisteína foi o marcador mais significativo em relação à DAP. Ocorreu associação entre redução do ITB com a elevação dos níveis pressóricos, das glicemias, da homocisteína, assim como diminuição das médias da FGe. Foi conclído que nos pacientes com DAP a hiperhomocisteinemia está associada à diminuição da FGe, ambas passíveis de prevenção, contribuindo na redução da morbimortalidade da DAP. A estreita associação da DAP com a FGe diminuída representou relevante contribuição do estudo. / Peripheral Artery (DAP) is the result of the atherosclerotic process involving the arteries of the superior and inferior limbs, abdominal aorta and its visceral branches. The objective was detect PAD, using the ankle brachial index (ABI), in patients ≥ 30 years old attended in the Unidade Docente - Assistencial of Angiology (UDA), correlating it with risk factors (RF) and estimated glomerular filtration rate (eGFR), with intention to describe the RF and association with chronic kidney disease. It was used a standard questionnaire and the ABI to identify patients with and without PAD. Laboratorial tests, as total cholesterol, triglycerides, HDL-c, LDL-c, glycemia, creatinine and homocysteine were correlated to ABI. Statistical analyses were done using the Statistical Package for the Social Sciences (SPSS) 16.0 program. The results had pointed to the importance of the ABI in the diagnosis of PAD, with degrees of mild, discrete, moderate and serious stenosis for the symptomatic patients, and the identification of the asymptomatic ones, making possible intervention in the RF and control of their complications. Tabagism was confirmed as the RF with most important odds ratio for PAD. The systolic and diastolic hypertension showed to be more significant than diabetes mellitus, as diseases associated to PAD. In laboratorial evaluation, the traditional blood markers for PAD: total cholesterol, triglycerides and glucose had shown statistics significance. Homocysteine was the marker most significant in PAD. Association between reduction of ABI with systolic and diastolic hypertension and glycemias occurred, as well as reduction of the averages of the eGFR. The conclusion was, in patients with PAD, hyperhomocysteinemia and decrease of eGFR are possible of prevention, contributing in the reduction of the morbimortality of PAD. The narrow association of decrease eGFR in patients with PAD represented excellent contribution of this study.

A Doença da Artéria Periférica (DAP) é o resultado do processo aterosclerótico das artérias dos membros superiores, inferiores, aorta abdominal e seus ramos viscerais. Nosso objetivo foi detectar a DAP correlacionando-a com fatores de risco (FR) e a filtração glomerular estimada (FGe) nos pacientes com ≥30 anos, assistidos na Unidade docente - assistencial de Angiologia (UDA) do Hospital Universitário Pedro Ernesto da Faculdade de Ciências Médicas - UERJ, com o intuito de descrever os FR e associação com doença renal crônica à DAP, a partir da aferição do índice tornozelo-braço (ITB); determinar a alteração da FGe por equações, relacionando-a à progressão da DAP. Foi usado um questionário padrão e o ITB para identificar os pacientes com e sem DAP. Correlacionou-se as variáveis laboratoriais, como os níveis séricos de colesterol, triglicerídeos, HDL-c, LDL-c, glicemia, homocisteína com a FGe e com o ITB. As análises estatísticas foram feitas pelo programa Statistical Package for the Social Sciences (SPSS) 16.0 Os resultados apontaram para a importância do ITB no diagnóstico da DAP, com configuração de graus de obstrução leve, discreta, moderada e grave para os sintomáticos, e a identificação dos assintomáticos, possibilitando intervenção nos fatores de risco demarcados e o controle de suas complicações. O tabagismo mostou-se como o FR com razão de risco mais importante para DAP. A hipertensão sistólica e a diastólica foram variáveis clínicas mais significativas que o diabetes mellitus. Os marcadores séricos tradicionais para DAP: colesterol total, triglicerídeos e glicemia mostraram significância estatística. A homocisteína foi o marcador mais significativo em relação à DAP. Ocorreu associação entre redução do ITB com a elevação dos níveis pressóricos, das glicemias, da homocisteína, assim como diminuição das médias da FGe. Foi conclído que nos pacientes com DAP a hiperhomocisteinemia está associada à diminuição da FGe, ambas passíveis de prevenção, contribuindo na redução da morbimortalidade da DAP. A estreita associação da DAP com a FGe diminuída representou relevante contribuição do estudo. / Peripheral Artery (DAP) is the result of the atherosclerotic process involving the arteries of the superior and inferior limbs, abdominal aorta and its visceral branches. The objective was detect PAD, using the ankle brachial index (ABI), in patients ≥ 30 years old attended in the Unidade Docente - Assistencial of Angiology (UDA), correlating it with risk factors (RF) and estimated glomerular filtration rate (eGFR), with intention to describe the RF and association with chronic kidney disease. It was used a standard questionnaire and the ABI to identify patients with and without PAD. Laboratorial tests, as total cholesterol, triglycerides, HDL-c, LDL-c, glycemia, creatinine and homocysteine were correlated to ABI. Statistical analyses were done using the Statistical Package for the Social Sciences (SPSS) 16.0 program. The results had pointed to the importance of the ABI in the diagnosis of PAD, with degrees of mild, discrete, moderate and serious stenosis for the symptomatic patients, and the identification of the asymptomatic ones, making possible intervention in the RF and control of their complications. Tabagism was confirmed as the RF with most important odds ratio for PAD. The systolic and diastolic hypertension showed to be more significant than diabetes mellitus, as diseases associated to PAD. In laboratorial evaluation, the traditional blood markers for PAD: total cholesterol, triglycerides and glucose had shown statistics significance. Homocysteine was the marker most significant in PAD. Association between reduction of ABI with systolic and diastolic hypertension and glycemias occurred, as well as reduction of the averages of the eGFR. The conclusion was, in patients with PAD, hyperhomocysteinemia and decrease of eGFR are possible of prevention, contributing in the reduction of the morbimortality of PAD. The narrow association of decrease eGFR in patients with PAD represented excellent contribution of this study.

No description available.