OBJECTIVES: To determine whether there is a decrease in renal cortical or medullary perfusion and oxygenation in a conscious large animal model of hyperdynamic septic shock with acute kidney injury. DESIGN: Interventional animal study. SETTING: University-affiliated research institute. SUBJECTS: Eight merino ewes. INTERVENTIONS: Sheep were surgically instrumented with pulmonary and renal artery flow probes in the renal cortex and medulla, combination fiber-optic probes comprising a fluorescence optode to measure tissue PO2, and a laser-Doppler probe to assess tissue perfusion. Sepsis was induced by infusion of live Escherichia coli for 24 hours followed by 24-hour recovery. MEASUREMENTS AND MAIN RESULTS: In unanesthetized normal sheep, resting levels of cortical and medullary tissue PO2 were 29.5 +/- 4.4 and 29.1 +/- 4.3 mm Hg, respectively. During infusion of E. coli, hyperdynamic sepsis developed with hypotension, tachycardia, increased cardiac output, increased renal blood flow, oliguria, decreased creatinine clearance, and increased serum creatinine. Renal oxygen delivery increased while renal oxygen consumption was unchanged. During sepsis, cortical tissue PO2 increased from 29.4 +/- 4.3 to 36.3 +/- 3.5 mm Hg (p <0.001), whereas medullary oxygenation decreased from 29.6 +/- 4.7 to 13.1 +/- 2.7 mm Hg (p <0.001). Cortical perfusion was not significantly changed, but medullary perfusion decreased (671 BPU [500-900 BPU] to 480 BPU [349-661 BPU]; geometric mean [95 CI]; p <0.001). CONCLUSIONS: In a large animal model of hyperdynamic sepsis, renal hyperemia was associated with preserved cortical oxygenation and perfusion, but decreased medullary oxygenation and perfusion. Medullary hypoxia due to intrarenal blood flow redistribution may be one of the factors causing acute kidney injury in sepsis.