Endothelial Dysfunction in Kidney Transplantation

Abstract

Kidney transplantation entails a high likelihood of endothelial injury. The endothelium is a target of choice for injury by ischemia-reperfusion, alloantibodies, and autoantibodies. A certain degree of ischemia-reperfusion injury inevitably occurs in the immediate posttransplant setting and can manifest as delayed graft function. Acute rejection episodes, whether T-cell or antibody-mediated, can involve the graft micro- and macrovasculature, leading to endothelial injury and adverse long-term consequences on graft function and survival. In turn, caspase-3 activation in injured and dying endothelial cells favors the release of extracellular vesicles (apoptotic bodies and apoptotic exosome-like vesicles) that further enhance autoantibody production, complement deposition, and microvascular rarefaction. In this review, we present the evidence for endothelial injury, its causes and long-term consequences on graft outcomes in the field of kidney transplantation.

Keywords: alloantibodies; apoptosis; autoantibodies; endothelial injury; kidney transplantation; necroptosis.

Figure 1

Factors contributing to endothelial dysfunction in transplantation. Ischemia-reperfusion injury that occurs at the time of transplantation can trigger endothelial apoptosis through caspase-3 activation which can in turn release apoptotic bodies with procoagulant activity. In addition, apoptotic endothelial cells also release apoptotic exosome-like vesicles that favor the recruitment of inflammatory cells (e.g., T cells) and the production of autoantibodies such as anti-perlecan/LG3 antibodies (anti-LG3). The synergistic interactions between cellular alloimmunity and autoimmunity, donor-specific antibodies (DSA), and autoantibodies [anti-LG3, anti-angiotensin II type 1 receptors (AT1R)] amplify microvascular damage, through complement-dependent (C4d deposition) or -independent pathways, which leads to permanent peritubular capillary rarefaction. Loss of peritubular capillaries favors chronic hypoxia, leading to overexpression of hypoxia inducible factor 1 α (HIF-1α), favoring transcription of fibrogenic genes such as transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). It also favors accumulation of collagen, α-smooth muscle actin (α-SMA) positive myofibroblasts and of fibrogenic mediators. These phenomena eventually lead to progressive interstitial fibrosis/tubular atrophy and renal graft dysfunction.