The studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury... Show moreThe studies in this thesis describe the systematical search for factors involved in the pathophysiology of human renal I/R injury. Many of the processes assumed to be involved in renal I/R injury based on animal studies could not be confirmed in our clinical study in humans. However, we found new evidence of complement activation and endothelial cell activation in human renal I/R injury. Moreover, there were large differences between deceased and living donor kidneys; brain dead donor kidneys have a unique proinflammatory cytokine release after reperfusion. Finally it appears that both brain dead and cardiac dead donor kidneys are not able to upregulate their metabolism-related genes upon reperfusion as living donor kidneys do, indicating that failure to restart metabolism may be a factor expanding I/R injury. All of these findings contribute to the understanding of renal I/R injury in humans and instigate the further search for therapeutical modalities to limit renal I/R injury. Show less
The main challenge of this thesis was to evaluate whether the reperfused heart induced systemic effects postoperatively, contributing to morbidity and mortality after cardiac surgery. We identified... Show moreThe main challenge of this thesis was to evaluate whether the reperfused heart induced systemic effects postoperatively, contributing to morbidity and mortality after cardiac surgery. We identified preexisting processes in patients with heart failure, such as complement activation and influx of inflammatory cells in the myocardium. These changes in their turn altered the post-reperfusion response of the myocardium after cardiac surgery. Moreover, preexisting low-grade endothelial cell activation predicted the development of post-cardiac surgery vasoplegia. No evidence was found for oxidative damage after reperfusion in contrast to the current theory. As expected, targeting the inflammatory resposne with sevoflurane resulted in attenuation of pro-inflammatory markers, although no cardioprotective effects were observed. A stepwise approach in future research via preclinical to clinical studies, and vice versa, is ne cessary to ensure the integration of advancements in pathophysiological science with clinical trials Show less
