Chronic transplant dysfunction: Etiological and pathophysiological aspects

Organ transplantation has saved the life of many people throughout the world, who suffered from end·stage organ failure. The University Hospital Rotterdam·Dijkzigt, is one of the Dutch organ transplant centers, in which kidney, heart and liver transplantation are performed. In close conjunction with hurdles encountered in clinical organ transplantation, experimental transplantation research has been for a long time one ofthe points ofinterestofthe Department of Surgery. Experimental work in small and large animal models to overcome the thresholds to successful intestinal transplantation has been of special interest for years. My scientific curiosity for the transplantation·field was provoked during participation as a student in a research project at the Laboratory for Experimental Surgery to investigate xenogeneic islet transplantation as therapy for diabetes mellitus. In addition to search for new transplant modalities, we also try to improve long. term graft survival as data show that clinical organ transplantation has not yet achieved its full potential on the long· term. Beyond one year post· transplantation, the half·life of organ grafts has little changed since the beginning ofthe transplantation.era. Long·term graft survival is predominantly hampered by chronic transplant dysfunction (CTD). So far, no drugs can prevent CTD and a therapeutic strategy is not within hand's reach, since causes and mechanisms leading to CTD are poorly known. Retransplantation is at present the only effective therapy. In '995, I first started experiments at the Laboratory for Experimental Surgery to gain insight into the etiology of CTD: The role of ischemia and surgery was shldied in an aorta transplantation modeL Participating in ongoing experiments, at the Departments of Medicine and Surgery, Monash University, Melbourne, Australia I investigated the pathogenesis of CTD after small bowel transplantation in a rat modeL From a clinical point of view, I continued experiments on the pathogenesis in the kidney and studied the effect of ischemia, surgery and genetics. TI,ese studies were carried out in close collaboration with the Departments of Paediatric Surgery and Pathology, Erasmus University and with the Department of Nephrology, University Hospital, Essen, Germany. This thesis outlines the problem of CTD, presents the results of the experimental studies mentioned above, and finally discusses tl,e results.