OPTIMIZING IMMEDIATE GRAFT FUNCTION IN KIDNEY TRANSPLANTATION

R. Thuillier¹, H. Lathelize¹, J. Paarkkinen², L. Vaahtera², T. Hauet^1
1Faculte De Medecine Et Pharmacie, Chu De Poitiers, Inserm U927, poitiers cedex/FRANCE, ², University of Helsinki, Helsinki/FINLAND

Body: Purpose: Kidney transplantations from deceased after cardiac arrest donors (DCD) suffer from ischemia reperfusion injury (IRI) and show increased occurrence of delayed graft function (DGF) and lower long term survival. Oxidative stress and NF-kB activation are well described elements of IRI. We evaluated the benefits of supplementing the current preservation protocol with curcumin, a potent antioxidant and NF-kB inhibitor.
Methods: We used an autologous DCD kidney transplantation model in Large White pigs. Kidneys undergo warm ischemia for 60 min before being preserved at 4°C for 24 hours using UW supplemented with Heparin. Cyclodextrin-complexed curcumin, a novel water soluble formulation, was added to the preservation solution.
Results: Curcumin supplementation greatly improved recovery of function: animals resumed urine production two days before controls, serum creatinine started recovering at day 5 (vs. day 11) and reached stable levels by day 11, while controls did not reach similar levels by day 30 (Fig.1). Animal survival was critically improved for the curcumin group (83.3% vs. 29% in controls, p<0.05) (Fig.2). Chronic graft fibrosis at 3 month, evaluated by Sirius Red staining (Fig 3), revealed that UW grafts had developed extensive injury (37.3 ± 2.8 %) while curcumin supplementation had prevented the lesion (7.1 ± 0.5 %). Preliminary Q-PCR data on tissues at this time (Fig 4) showed curcumin protection against fibrosis marker PAI-1 as well as epithelial to mesenchymal markers Vimentin and S100A4. Curcumin grafts also showed decreased expression of inflammation markers TNF-α, IL1Rn and C3, as well as oxidative stress marker p47. Finally, decrease of Relaxin, an anti-fibrotic, was prevented. Conclusion: Curcumin supplementation of UW in a pre-clinical transplantation model with stringent ischemia reperfusion injury rescued kidney grafts from an unfavorable prognosis. Early graft function was recovered faster and survival was substantially improved. As curcumin has proved well tolerated and nontoxic, this preservation strategy shows great promise for translation to clinical kidney transplantations: it requires little addition to current protocols and although further analysis is needed to define the mechanisms involved, curcumin supplementation can have substantial benefits to graft outcome.

Disclosure: All authors have declared no conflicts of interest.