Chronic kidney disease and early vascular ageing : pinpointing culprits of injury and targets for intervention

Chronic kidney disease (CKD) is a progressive non-communicable disease, and a clinical model of premature ageing. Approximately 1 in 10 people globally have CKD, defined as abnormalities of kidney structure and/or function that persist for more than three months. Due to an increase in prevalence of diabetes and hypertension, the major CKD aetiologies, this figure is expected to escalate in the next twenty years. Patients present a heightened cardiovascular (CV) risk, with 40-50% of deaths in advanced CKD attributed to CV disease. An early vascular ageing (EVA) phenotype contributes to the high CV burden, which includes structural hallmarks such as vascular calcification (VC), endothelial dysfunction, and fibrosis. Current treatment strategies aim to slow progression and target complications of CKD; thus, there is an urgent need to better understand molecular mechanisms that promote EVA to identify novel targets that can be therapeutically modulated. This would reduce the high burden on healthcare systems and simultaneously reduce the number of patients that require life-saving renal replacement therapy in the form of dialysis or kidney transplantation (KTx). The overall aim of this thesis was to investigate the effects of the uremic milieu on components of the EVA phenotype in CKD. Using a translational approach, a combination of epidemiological clinical datasets, an in vivo animal model of CKD-induced VC, ex vivo human tissue from ESKD patients, and an in vitro cell model were used to answer the specific research questions for each study. In Article I, we studied the relationship between five established uremic toxins with lipid profile markers. The results from this study demonstrated counterintuitive independent, negative associations between indole-3 acetic acid, trimethylamine N-oxide (TMAO), and phenylacetylglutamine (PAG) with specific lipid profile markers, which suggest not all interactions between uremic toxins and CKD-related risk factors are detrimental. In Article II, senescent cell burden and ...