Background: Acute Kidney Injury is common, serious with no specific treatment. Ischemia-reperfusion is a common cause of acute kidney injury. Clinical trials suggest that pre-operative erythropoietin or remote ischemic preconditioning may have a renoprotective effect. Study Design: Using a porcine model of warm-ischemia-reperfusion induced acute kidney injury (40 min bilateral cross-clamping of renal arteries, 48h reperfusion) we examined the renoprotective efficacy of erythropoietin (1000 iu/kg i.v.) or remote ischemic preconditioning (3x cycles, 5 min inflation/deflation to 200mm Hg of a hind-limb sphygmomanometer cuff). Results: Ischemia-reperfusion induced significant kidney injury at 24 and 48h (2, 1df, >10 for 6/7 histopathological features). At 2h, a panel of biomarkers including plasma creatinine, NGAL and IL-1β, and urinary albumin:creatinine could be used to predict histopathological injury. Ischemia-reperfusion increased cell proliferation and apoptosis in the renal cortex but, for pre-treated groups, the apoptotic cells were predominantly intratubular rather than interstitial. At 48h reperfusion, plasma IL-1β and the number of subcapsular cells in G2-M arrest were reduced after preoperative erythropoietin, but not after remote ischemic preconditioning. Conclusions: These data suggest an intra-renal mechanism acting within cortical cells that may underpin a renoprotective function for pre-operative EPO and, to a limited extent, remote ischemic preconditioning. Despite equivocal longer-term outcomes in clinical studies investigating EPO as a renoprotective agent in AKI, optimal clinical dosing and administration have not been established. Our data suggest further clinical studies on the potential renoprotective effect of EPO and remote ischemic preconditioning are justified