Kidney xenotransplantation

Abstract

Xenotransplantation using pigs as donors offers the possibility of eliminating the chronic shortage of donor kidneys, but there are several obstacles to be overcome before this goal can be achieved. Preclinical studies have shown that, while porcine renal xenografts are broadly compatible physiologically, they provoke a complex rejection process involving preformed and elicited antibodies, heightened innate immune cell reactivity, dysregulated coagulation, and a strong T cell-mediated adaptive response. Furthermore, the susceptibility of the xenograft to proinflammatory and procoagulant stimuli is probably increased by cross-species molecular defects in regulatory pathways. To balance these disadvantages, xenotransplantation has at its disposal a unique tool to address particular rejection mechanisms and incompatibilities: genetic modification of the donor. This review focuses on the pathophysiology of porcine renal xenograft rejection, and on the significant genetic, pharmacological, and technical progress that has been made to prolong xenograft survival.

Figure 1. Phases of kidney xenograft rejection

A, Several factors contribute to hyperacute rejection of wild-type xenografts, but the key events are the binding of preformed anti-αGal antibodies (Ab) to xenograft vascular endothelial cells and subsequent activation of complement. HAR occurs within hours and can be prevented by deletion of αGal (GTKO) or transgenic expression of human complement-regulatory proteins (hCRPs). B, Acute humoral rejection of GTKO xenografts is also mediated by antibodies, in this case anti-non-Gal, but is a more prolonged process (days to weeks) which appears to involve the gradual development of a chronic pro-coagulant and pro-inflammatory vascular environment.

Figure 2. Donor genetic modification to prevent kidney xenograft rejection

The targets of genetic modification are shown as filled boxes. Abbreviations: CIITA-DN, dominant-negative class II transactivator; CRP, complement regulatory protein; GnT-III, N-acetylglucosaminyltransferase III; GTKO, GalT knockout; h: human; HO-1, hemoxygenase-1; HT, H-transferase; Neu5Gc-KO, N-glycolylneuraminic acid knockout; HLA, human leukocyte antigen; p: pig; shTNFR1, soluble human TNF receptor 1; Tg: transgenic; TFPI, tissue factor pathway inhibitor; TM, thrombomodulin; TRAIL, TNF-related human apoptosis-inducing ligand.