Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia-reperfusion injury.
BACKGROUND
Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model.


METHODS
The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW). The anti-Xa compound was injected intravenously before warm ischaemia and used during cold storage, and its effects were compared with those of intravenous injection of unfractionated heparin (UFH) before warm ischaemia and use during cold storage, or use of UW alone during cold storage.


RESULTS
At 3 months after transplantation, anti-Xa treatment improved recovery of renal function and chronic serum creatinine levels compared with UW and UFH (mean(s.e.m.) 89(4), 250(4) and 217(8) µmol/l respectively). The anti-Xa treatment also reduced fibrosis, and decreased tissue expression of markers of the epithelial-mesenchymal transition compared with UW and UFH. Cleaved protease-activated receptor 2 was overexpressed in the UW group compared with the anti-Xa and UFH groups. Leucocyte infiltrates were decreased in the anti-Xa group compared with the UW and UFH groups. Macrophage invasion was also decreased by anticoagulation treatment.


CONCLUSIONS
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.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1082, Poitiers, France; Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France.
S
S
Tillet
S
S
Giraud
P O
PO
Delpech
R
R
Thuillier
V
V
Ameteau
J M
JM
Goujon
B
B
Renelier
L
L
Macchi
T
T
Hauet
G
G
Mauco
D000241:Adenosine / Q000494:pharmacology; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D003250:Constriction; D016207:Cytokines / Q000378:metabolism; D000077425:Fondaparinux; D005978:Glutathione / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D016030:Kidney Transplantation / Q000379:methods*; D007962:Leukocytes / Q000187:drug effects; D009393:Nephritis / Q000503:physiopathology; D019188:Organ Preservation Solutions / Q000494:pharmacology; D011134:Polysaccharides / Q000494:pharmacology*; D011887:Raffinose / Q000494:pharmacology; D015427:Reperfusion Injury / Q000517:prevention & control*; D013552:Swine; D014182:Transplantation, Autologous; D052096:Warm Ischemia / Q000379:methods
D000925:Anticoagulants; D016207:Cytokines; D007328:Insulin; D019188:Organ Preservation Solutions; D011134:Polysaccharides; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D005978:Glutathione; D000077425:Fondaparinux; D000241:Adenosine; D011887:Raffinose