Novel approaches in complement profiling; application in kidney transplantation

The first choice for patients with end-stage kidney failure is transplantation. Complement activation plays an important role in the cause of kidney failure after transplantation. This is a defense mechanism of the human body against foreign cells like bacteria, but also against a transplanted kidney. In this thesis we explored the pathomechanisms of the complement system in kidney transplant recipients, focusing on both systemic and cellular complement activation. In the first part of this thesis we found that the presence of the complement proteins properdine and C5b-9 in the urine are strongly associated with kidney failure after transplantation. Thereafter we investigated the mechanism of properdin mediated complement activation and found molecular structures that are able to interact with properdin and described several complement activation inhibitors.
In the second part of this thesis we focused on complement activation mediated by antibodies, because an important cause of rejection is the presence of antibodies against the donor kidney. We developed a method to isolate endothelial cells from perfused human donor kidneys and performed donor-recipient crossmatch assays using these cells. We show that this test, next tot he detection of antibodies, also effectively monitors the removal of antibodies from the blood of patients. At last we showed that it could very well be that complement-independent mechanisms also play an important role in the development of antibody mediated rejection.
The results described in this thesis could add important value to a better prediction of whether an individual patient has a higher or a lower risk of rejection and that immunosuppresive medicine can be adjusted if required.