Complement Therapeutics in the Multi-Organ Donor: Do or Don't?

Abstract

Over the last decade, striking progress has been made in the field of organ transplantation, such as better surgical expertise and preservation techniques. Therefore, organ transplantation is nowadays considered a successful treatment in end-stage diseases of various organs, e.g. the kidney, liver, intestine, heart, and lungs. However, there are still barriers which prevent a lifelong survival of the donor graft in the recipient. Activation of the immune system is an important limiting factor in the transplantation process. As part of this pro-inflammatory environment, the complement system is triggered. Complement activation plays a key role in the transplantation process, as highlighted by the amount of studies in ischemia-reperfusion injury (IRI) and rejection. However, new insight have shown that complement is not only activated in the later stages of transplantation, but already commences in the donor. In deceased donors, complement activation is associated with deteriorated quality of deceased donor organs. Of importance, since most donor organs are derived from either brain-dead donors or deceased after circulatory death donors. The exact mechanisms and the role of the complement system in the pathophysiology of the deceased donor have been underexposed. This review provides an overview of the current knowledge on complement activation in the (multi-)organ donor. Targeting the complement system might be a promising therapeutic strategy to improve the quality of various donor organs. Therefore, we will discuss the complement therapeutics that already have been tested in the donor. Finally, we question whether complement therapeutics should be translated to the clinics and if all organs share the same potential complement targets, considering the physiological differences of each organ.

Brain death-induced lung injury is complement dependent, with a primary role for the classical/lectin pathway

“…Moreover, they showed C4d deposition in hearts from human brain‐dead donors, which further supports involvement of the CP 25 . Nevertheless, it should be noted that dissimilarities between physiology of organs might lead to different ways of complement activation 26 . Therefore, it remains important to study contribution of different complement components in the organ of interest.…”

“…A possible benefit of systemic treatment in the organ donor, is the ability to simultaneously treat all potential donor organs, damaged by the BD process. However, it should be noted that not all organs might share the same target to inhibit BD‐induced complement activation, thus favoring local treatment modalities 26 . Earlier studies described pulmonary alveolar type II epithelial cells as capable to secrete complement proteins C2, C3, C4, C5, and factor B 29 .…”

Blocking Complement Factor B Activation Reduces Renal Injury and Inflammation in a Rat Brain Death Model

“…Thus, factor B seems to be a promising target to improve renal transplant outcome, in both the donor as well as in the recipient. However, treatment of the donor might be more beneficial than of the recipient, since the complement system is already activated in the donor and as has been shown to affect the function of the renal allograft (11, 32). Taken together, these results create a new window of opportunity for complement-targeted therapies in the renal transplantation setting.…”

Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials

“…In 2019, in Europe, 30% of potential donors are ECD and a similar percentage of these kidneys are discarded annually. It's well recognized that kidneys from ECD correlated with approximately 2-fold increased risk of DGF, acute rejection, and graft loss (14,15) (Figure 1).…”