Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment

Abstract

Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.

Keywords: Acute kidney injury; Anti-inflammatory strategies; Delayed graft function; Inflammatory response; Innate and adaptive immune response; Ischemia-reperfusion.

Figure 1

Biological consequences of ischemia-reperfusion.

Figure 2

Rolling, firm adhesion and diapedesis of leukocytes. Leukocyte rolling is initiated by increase in endothelial P-selectin and its interaction with the leukocyte receptor PGSL-1; integration of integrins CD11a/CD18 with endothelial ICAM-1 results in leukocyte adherence; Leukocyte transmigration, facilitated by PECAM-1. PGSL-1: P-selectin glycoprotein 1-ligand; ICAM-1: Intercellular adhesion molecule 1; PECAM-1: Platelet endothelial cell adhesion molecule-1.

Figure 3

Schematic view of innate inflammatory response. PAMPs: Pathogen associated molecular patterns; DAMPs: Danger associated molecular patterns; TLRs: Toll-like receptors; TRAF6: TNF receptor-associated factor 6; MyD88: Myeloid differentiation primary response 88; TIRAP: Toll-interleukin 1 receptor (TIR) domain containing adaptor protein; TRAM: TRIF-related adaptor molecule; TRIF: TIR domain containing adaptor protein inducing interferon β; IRAK1: Interleukin 1- receptor-associated kinase 1; TBK1: TANK binding kinase 1; IKK: Inhibitor of nuclear factor kappa-B kinase; NFκB: Nuclear factor kappa B; MAP3: MAP3 kinase; IFR3: Interferon regulatory factor 3.

Figure 4

Adaptive immunity. Interrelationship between T and B cells. TCR: T cell receptor; MHC: Major histocompatibility complex; BCR: B cell receptor.