Complement modulation to improve donor organ quality: interventions during brain death and normothermic machine perfusion

In The Netherlands, every year about 2.000 patients develop end-stage renal disease, which means the kidneys are functioning below 10% of their normal function. Patients with end-stage renal disease are therefore dependent on dialysis as a form of renal replacement therapy. The burden of dialysis is high and patient survival is poor, which makes renal transplantation the optimal treatment for patients with end-stage renal disease. However, the number of renal transplantations performed is limited by the persistent shortage of donor organs. Donor kidneys are retrieved from different types of donors: living donors, donation after circulatory death and donation after brain death. Worldwide, most kidneys are retrieved from brain-dead donors. Depending on the donor-type there is a significant variability in the quality of kidneys that are used for transplantation, which results into differences in outcome. Kidneys derived from brain-dead donors show inferior results compared to kidneys derived from living donors, because of the pathophysiological changes in brain-dead donors. Brain death elicits a systemic inflammatory response which results in activation of the complement system, an important component of innate immunity. Activation of the complement system during brain death results in renal injury and inflammation prior to transplantation.

Jager and colleagues investigated which complement pathways contribute to brain death-induced renal injury. Besides unraveling the pathophysiological mechanisms, multiple points of intervention are described. In addition, Jager and colleagues showed that inhibition of complement during brain death resulted in less renal injury and inflammation. Lastly, this thesis describes a potential window of opportunity for the use of complement therapeutics during normothermic machine perfusion, which is used as a preservation method during the time in between donor organ retrieval and actual transplantation into the recipient. However, more clinical studies need to be performed to demonstrate that inhibition of the complement system prior to transplantation improves renal transplant outcome.