Critical role of complement in antibody mediated rejection in kidney transplantation

Abstract

Antibody-mediated rejection (AMR) represents a major challenge in kidney transplantation, significantly contributing to tissue injury and graft failure. AMR is primarily driven by donor-specific alloantibodies (DSAs), which recognize and bind to specific target antigens present within the transplanted kidney tissue. Upon binding, these DSAs commonly initiate activation of the complement system within the graft. The activation of the complement cascade sets off a powerful inflammatory response characterized by the recruitment and activation of immune cells, endothelial damage, and subsequent tissue injury. This inflammation underlies many clinical and histological manifestations of AMR, making complement activation a critical player in the disease process. Advancements in our understanding of how complement pathways contribute to kidney graft injury have opened new avenues for therapeutic intervention. Recent research has facilitated the development and application of novel therapies specifically designed to inhibit complement activation. Such targeted complement-inhibitory strategies have shown promise in improving graft outcomes by inhibiting complement-mediated damage and extending graft survival. This review comprehensively discusses the critical role of complement activation in inducing kidney graft injury with a focus on its role in AMR. By elucidating the detailed mechanisms and contributions of complement pathways, the review seeks to enhance the understanding necessary for developing targeted therapeutic interventions to prevent or treat AMR effectively.

Keywords: Complement; Donor-specific antibodies; Kidney; Allograft; Rejection; Graft failure

Core Tip: Antibody-mediated rejection (AMR) is a significant barrier to successful kidney transplantation, driven primarily by donor-specific alloantibodies. These antibodies activate complement pathways within the transplanted kidney, leading to severe inflammatory responses, endothelial injury, and tissue damage. Understanding the complement system’s critical role in AMR has led to innovative therapies aimed at inhibiting complement activation. Such complement-targeted strategies show potential in reducing inflammation, preventing graft injury, and improving overall graft survival. This review highlights the central contribution of complement activation in AMR, emphasizing therapeutic advancements and the importance of complement inhibition as a promising approach for preventing and managing rejection.