Ischemia-Reperfusion Injury in Kidney Transplantation: Mechanisms and Potential Therapeutic Targets

Abstract

Kidney transplantation offers a longer life expectancy and a better quality of life than dialysis to patients with end-stage kidney disease. Ischemia-reperfusion injury (IRI) is thought to be a cornerstone in delayed or reduced graft function and increases the risk of rejection by triggering the immunogenicity of the organ. IRI is an unavoidable event that happens when the blood supply is temporarily reduced and then restored to an organ. IRI is the result of several biological pathways, such as transcriptional reprogramming, apoptosis and necrosis, innate and adaptive immune responses, and endothelial dysfunction. Tubular cells mostly depend on fatty acid (FA) β-oxidation for energy production since more ATP molecules are yielded per substrate molecule than glucose oxidation. Upon ischemia-reperfusion damage, the innate and adaptive immune system activates to achieve tissue clearance and repair. Several cells, cytokines, enzymes, receptors, and ligands are known to take part in these events. The complement cascade might start even before organ procurement in deceased donors. However, additional experimental and clinical data are required to better understand the pathogenic events that take place during this complex process.

Keywords: IRI; complement; graft; injury; ischemia; kidney transplantation; reperfusion.

Figure 1

Pathophysiology of ischemia–reperfusion injury (IRI).

Figure 2

Complement system activation during IRI. IRI stimulates the complement system by releasing endogenous ligands (DAMPs) from acutely wounded tissue. The formation of the membrane attack complex (MAC) causes immediate damage to the kidney by inducing apoptosis in epithelial tubular cells. During IRI, tubular epithelial cells overexpress collectin-11 (CL11), which can activate mannan-binding serin protease (MASP). The main pathways involved in abnormal complement system activation during renal IRI are lectin and alternative. Higher serum levels of C5a and sC5b-9 were associated with a higher risk of rejection. C3aR/C5aR1 signaling is required for dendritic cells (DCs) maturation and the Th1 response. DAMPs—damage-associated molecular patterns; DBD—donation after brain death; DCD—donor after circulatory death.