Complement activation in renal transplantation : from donor to recipient

Although patients with end-stage renal disease can be maintained with dialysis therapy, the superiority of patient survival with renal transplantation makes transplantation the preferred method of renal replacement therapy. Although kidney transplantation has become the first choice of treatment for these patients, due to donor organ shortage, patients are still dying on the waiting list. The major donor pool consists of kidneys recovered from deceased braindead donors (DBD) although living donation and donation after cardiac death (DCD) have emerged as alternative sources. Long-term renal allograft survival of deceased donor kidneys is determined by different variables including donor condition and age, kidney preservation methods, human leukocyte antigen matching, duration of cold and warm ischemia, reperfusion injury and acute rejection (1-3). Independent from these variables, the state of brain death (BD) in the donor has been established as a risk factor affecting transplant outcome. Kidneys from brain-dead donors have an inferior transplant function, decreased survival rates and a higher risk to develop acute rejection as compared to kidneys obtained from healthy living (un)related donors (4;5). During the last decades, several groups have focused on the influence of donor BD on kidney graft viability and survival rates after renal transplantation in experimental and clinical settings. Our group and others have observed systemic and local immune activation after BD which might be, at least in part, responsible for the renal injury found in brain-dead donors (6;7). We hypothesized that a substantial part of this inflammatory response can be ascribed to activation of the complement system which has been shown to play an important role in the pathogenesis of renal transplant related injury. This thesis focuses on complement mediated renal injury of deceased donor kidneys in experimental and clinical kidney transplantation.
In Chapter 1, the current knowledge of complement activation in cellular and humoral rejection, renal ischemia-reperfusion injury (IRI) and donor BD is outlined. During humoral rejection, the interaction between B-cell responses and classical complement pathway activation has been acknowledged by the presence of C4d-positive peritubular capillaries (8). Cellular rejection is likely to be mediated by complement through activation of antigen presenting cells (APCs). C3 deficient APCs have an impaired potency to stimulate alloreactive T-cells. Also, C3a and C5a are able to regulate the T-cell response by stimulation of APCs through the C3a and C5a receptor (9;10). Renal IRI is an inevitable consequence of kidney transplantation. In mice it was demonstrated that deficiency of C3, C5 and C6 significantly reduced renal IRI. Evidence exists that both C5a and the membrane attack complex are involved in the pathogenesis of renal IRI (11;12). In experimental renal transplantation, a major breakthrough was the finding that absence of donor C3 in transplanted renal allografts greatly improved kidney allograft survival after transplantation. In contrast, when kidneys from wild-type mice were transplanted into C3 deficient recipients this was not found to be protective. These results indicate that not circulating C3 in the recipient but locally produced C3 by the donor kidney is an important mediator of renal transplant related injury (13;14). These results put the role of complement activation in an importantly different perspective, as now the donor is such an important factor since most organs are not derived from living, but deceased donors.

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