Oxidative stress and inflammation as a response to glucose exposure and dialysis

Abstract: The main player of this thesis is glucose, both on a cellular level and with a clinical approach. Too much or wrongly handled glucose contributes to increased inflammation and oxidative stress, which is reinforced by the negative influences of uraemia and dialysis treatment. In addition, trace element status is also affected in dialysis patients. Hyperglycaemia contributes to glucose degradation products (GDP) and advanced glycation end product (AGE), inducing inflammation, oxidative stress and cell death through activation of several pathways. We investigated GDP content in commercially available infusion fluids and compared patients receiving those with a control group, by looking at GDPs and AGE levels, and inflammatory response. We also investigated hyperglycaemia and GDPs impact with or without citrate addition on protein kinase C (PKC) and adhesion molecule expression, cell death and secretion of cytokines. A transwell model was used to analyse neutrophil migration across endothelial cell layer. This thesis also had a clinical approach, looking at inflammation, oxidative stress and AGE formation, in combination with trace elements in diabetic- and non-diabetic dialysis patients. All investigated infusion fluids contained GDPs in varying concentrations, some similar to LC50 values of neutrophils in vitro. Both GDPs and AGE could be found in patients’ blood and urine after infusion. Furthermore, GDPs and hyperglycaemia increased cell death of both neutrophils and endothelial cells. They also increased endothelial expression of PKC, adhesion molecules and cytokines, reduced by the addition of citrate. There was a significant lack of the trace elements selenium and rubidium generally in dialysis patients compared with healthy subjects and a significant correlation between low plasma selenium and high markers of oxidative stress in diabetic dialysis patients. Other trace elements, which can contribute to increased oxidative stress, such as chromium and copper were increased in hemodialysis patients compared with healthy subjects. In conclusion, a therapeutic aspect is necessary, looking at the possibilities of using citrate and taking control over trace element reduction and supplementation. Further work improving dialysis fluids, might be a way of controlling these substances and administrate them where they might have an immediate effect, i.e. on the blood cells and the endothelial cell