Childhood obesity-related inflammation and vascular injury - Impact on the kidney
ISPUP; Centro Hospitalar de São João, EPE;
Background: Childhood obesity is achieving pandemic proportions. Several epidemiologic studies show that obesity increases the risk of renal disease in the general population. Nevertheless, the mechanisms that determine renal function impairment in obese, otherwise healthy, children remain incompletely understood. Besides hemodynamic factors that are related to obesity, inflammatory and metabolic effects have been suggested to be implicated in the initiation of renal damage. Adipose tissue renin-angiotensin-aldosterone system (RAAS) could be an additional potential causal link for the metabolic derangements in obesity. Oxidative stress could contribute as a potential mechanism linking obesity with endothelial dysfunction because oxidation reactions are crucial in the pathogeny of atherogenesis. Main problem: To clarify the impact of childhood obesity and its consequences on the kidney. Research question and aims: The main aim of this project is to characterize renal function indexes/markers, inflammation, redox environment, RAAS activity and carotid-femoral pulse wave velocity (PWV) in a population of 8-year-old children and to compare these parameters according to the presence of overweight and obesity. As specific aims, we intend to 1) investigate whether changes in various renal function indexes/markers can be detected, at 8 years of age, in excess weight children when compared to normal weight controls; 2) quantify plasma and urinary markers of inflammation and oxidative stress and to quantify differences in the levels of these markers in excess weight children when compared to normal weight; 3) characterize the activity of the RAAS in excess weight and normal weight children; 4) assess PWV in excess weight and lean children, and to associate these findings with the presence of other cardiovascular risk factors and altered renal function parameters; 5) associate plasma and urinary markers of inflammation and oxidative stress, and RAAS activity with renal function markers and to appreciate to which extent they mediate the effect of obesity on renal impairment. Methods: We will conduct a cross-sectional study in children that have been followed since birth in a previously established cohort study (Geração XXI). Our findings will be analyzed in light of the prospectively gathered data from that cohort. We will study a subgroup of the initial cohort, of about 300 eight-year-old children, who will be evaluated in 2013-2014. The children will initially be included in one of three defined groups (normal weight, overweight and obese group) according to a previous evaluation at 4 years of age. The recruitment will be organized targeting a scheduled visit within 1 month of the childs 8th birthday. Evaluation will comprise a general physical examination and anthropometric data collection (height, weight, waist circumference, tetrapolar bioimpedance analysis and blood pressure evaluation). Blood samples will be obtained while subjects are fasting and 24-hour urine and random morning midstream urine specimen will also be collected. Cardiac evaluation will include 12-lead electrocardiogram, PWV analysis and 24-hour ambulatory arterial pressure measurement. Expected results: We expect to characterize the association of obesity and overweight with altered renal function parameters and with a state of increased inflammation and oxidative stress. Moreover, we intend to characterize the RAAS profile in excess weight and normal weight children. We expect to show that urinary angiotensinogen can be used as a marker of intrarenal activity of RAAS in obese children. Ultimately, we expect to be able to report that obesity derangements associate with altered renal function parameters. The likelihood of success of the projects is supported by the multidisciplinary nature of the team, involving experts in the main topics of this project, including a large experience in methodological aspects related with cohort studies, previous research work by the Pharmacology team in humans (heart failure patients) covering the pathways to be studied here, clinicians specialized in pediatric nephrology and child nutrition, and previously established collaborations with two international authorities in their own areas (Franz Schaefer and Dulce Casarini) with whom there has been co-authorship and a training probation period at the laboratory. The project also intends to promote the improvement of human resources on both technical and scientific aspects, supporting the development of post-graduation theses, writing of manuscripts, and presentation of the final results at national and international meetings. The project will also promote an exchange of ideias with external consultants, recognized as experts in the area of research of the project.