Abstract Body (Do not enter title and authors here): Background: Acute kidney injury (AKI) is a major unresolved complication of cardiac surgery, particularly in patients with pre-existing heart failure (HF). Mechanistic insight has been limited by the lack of large animal models replicating this complex clinical scenario. We developed a novel ovine model of HF with continuous, region-specific assessment of renal perfusion and oxygenation before, during, and after cardiopulmonary bypass (CPB).

Methods: Merino ewes (30-45 kg) were instrumented to continuously measure cardiac output (CO), mean arterial pressure (MAP), renal blood flow (RBF), renal oxygen delivery (RDO₂), and renal cortical and medullary perfusion and oxygenation (PO₂) across the pre- (conscious), intra- (anesthetized) and post-CPB (conscious) phases. HF was induced via coronary artery ligation and defined by ≥30% increase in heart rate and ≥30% reduction in left ventricular ejection fraction. HF (n=9) and healthy control (n=8) animals underwent 2 h of CPB with aortic cross-clamp (pump flow 2.4 L/min/m², target MAP 70 mmHg), followed by 48 h recovery.

Results: Compared to the pre-CPB (conscious) state, CPB reduced RBF and RDO₂ similarly in both groups (RBF: −56% HF, −55% control; RDO₂: −64% HF, −68% control; all p<0.01). Renal medullary perfusion and PO₂ also declined in both groups during CPB (perfusion: HF −71%, p=0.02; control −56%, p=0.08; PO₂: HF −42%, p=0.03; control −46%, p=0.5), with no significant intergroup differences. However, by 48 h post-CPB, medullary PO₂ had recovered in controls but remained markedly suppressed in HF animals (8.0 ± 3.7 vs 30.6 ± 5.5 mmHg, p=0.02), despite similar MAP, CO, RBF, cortical perfusion, and cortical PO₂. Postoperative AKI was more frequent in HF animals (55% vs 12.5%, OR 8.75). Across all animals, those with AKI had lower post-CPB medullary PO₂ than those without AKI (18.7 ± 3.5 vs 31.3 ± 3.5 mmHg, p=0.04). Conventional markers (urine output, creatinine clearance) did not differ significantly between groups at any stage, underscoring their limited sensitivity to early, region-specific injury.

Conclusion: This is the first large-animal model to replicate the perioperative course of cardiac surgery with CPB in the setting of heart failure, enabling continuous, region-specific monitoring of renal oxygenation. Persistent medullary hypoxia emerged as a key driver of postoperative AKI, highlighting a novel and potentially targetable mechanism in high-risk patients with HF.