Ischaemia-reperfusion injury: a major protagonist in kidney transplantation

Abstract

Ischaemia-reperfusion injury (IRI) is a frequent event in kidney transplantation, particularly when the kidney comes from a deceased donor. The brain death is usually associated with generalized ischaemia due to a hyperactivity of the sympathetic system. In spite of this, most donors have profound hypotension and require administration of vasoconstrictor agents. Warm ischaemia after kidney vessels clamping and the cold ischaemia after refrigeration also reduce oxygen and nutrients supply to tissues. The reperfusion further aggravates the state of oxidation and inflammation created by ischaemia. IRI first attacks endothelial cells and tubular epithelial cells. The lesions may be so severe that they lead to acute kidney injury (AKI) and delayed graft function (DGF), which can impair the graft survival. The unfavourable impact of DGF is worse when DGF is associated with acute rejection. Another consequence of IRI is the activation of the innate immunity. Danger signals released by dying cells alarm Toll-like receptors that, through adapter molecules and a chain of kinases, transmit the signal to transcription factors which encode the genes regulating inflammatory cells and mediators. In the inflammatory environment, dendritic cells (DCs) intercept the antigen, migrate to lymph nodes and present the antigen to immunocompetent cells, so activating the adaptive immunity and favouring rejection. Attempts to prevent IRI include optimal management of donor and recipient. Calcium-channel blockers, l-arginine and N-acetylcysteine could obtain a small reduction in the incidence of post-transplant DGF. Fenoldopam, Atrial Natriuretic Peptide, Brain Natriuretic Peptide and Dopamine proved to be helpful in reducing the risk of AKI in experimental models, but there is no controlled evidence that these agents may be of benefit in preventing DGF in kidney transplant recipients. Other antioxidants have been successfully used in experimental models of AKI but only a few studies of poor quality have been made in clinical transplantation with a few of these agents and we still lack of unambiguous demonstration that pre-treatment with these antioxidants can attenuate the impact of IRI in kidney transplantation. Interference with the signals leading to activation of innate immunity, inactivation of complement or manipulation of DCs is a promising therapeutic option for the near future.

Keywords: acute kidney injury; delayed graft function; dendritic cells; innate immunity; ischaemia reperfusion.