Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia–reperfusion injury

Abstract

Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.

Inhibition of coagulation proteases Xa and IIa decreases ischemia–reperfusion injuries in a preclinical renal transplantation model

“…Indeed, in this previous study, Fondaparinux was injected before warm ischemia and added in the UW preservation solution, 14 whereas here EP217609 was added only in the UW preservation solution. This procedure avoids intravenous administration and reduces required amounts of compound.…”

“…Moreover, UW control groups in these two studies are not comparable. In the Fondaparinux study, 14 animals of the UW group received an UFH injection before warm ischemia, whereas, in order to conform to clinical constraints, this was not the case here. Of note, a previous study with our porcine model suggested that pre-warm ischemia UFH injection could improve organ recovery, with lower PNF.…”

“…15 We also demonstrated that the use of unfractionated heparin (UFH), a non-synthetic anticoagulant which exhibits pharmacokinetic and biological limitations including induction of thrombocytopenia, 16 showed less benefits compared to more specific Melagatran and Fondaparinux. 12,13,14 In view of our previous findings, it appeared judicious to evaluate the impact of EP217609, an innovative powerful dual-action anticoagulant targeting two proteases factors IIa and Xa.…”

“…However, our laboratory previously demonstrated that the use of anti-IIa (Melagatran) or anti-Xa (Fondaparinux) molecules during graft preservation could limit early and chronic lesions of transplanted kidneys. 12,13,14 In addition, another group showed that Fondaparinux reduces IRI-induced expression of pro-inflammatory cytokines/chemokines as well as neutrophils invasion in a mice kidney IR model. 15 We also demonstrated that the use of unfractionated heparin (UFH), a non-synthetic anticoagulant which exhibits pharmacokinetic and biological limitations including induction of thrombocytopenia, 16 showed less benefits compared to more specific Melagatran and Fondaparinux.…”

“…17 Herein, we investigated, in a preclinical pig autotransplanted kidney model, the benefits of EP217609 (hereafter designated EP) against a high level of injury induced by a period of warm ischemia prior to organ collection followed by flush and cold ischemia preservation, mimicking injuries observed in DCD situation. We used a clinically relevant and ethically appropriate porcine model, without anticoagulation before warm ischemia (in contrast of our previous study 14 ), with addition of the anticoagulant EP molecule, only during the ex vivo flush and cold storage of the collected kidney. This porcine model offers a very high degree of correlation to the clinical situation.…”