Reversing Renal Medullary Hypoxia and Acute Kidney Injury in Sepsis

Sepsis is the main cause of death in intensive care units worldwide. Acute kidney injury (AKI) develops in up to 50% of septic patients leading
to increased mortality (up to 40%). There are no therapies for septic AKI, apart from dialysis, which is invasive and expensive and is not a cure
for AKI. A major barrier to the discovery of new therapies for septic AKI is the lack of animal models that replicate the complex
pathophysiology of human septic AKI.
We have established a clinically relevant ovine model of sepsis that has a similar phenotype to human septic AKI. In recent pioneering studies,
we found that in early sepsis there is ischaemia and hypoxia in the renal medulla, before AKI develops. Excitingly, we have new supporting
evidence that a direct renal arterial infusion of the antioxidant agent, tempol, prevents medullary ischaemia and hypoxia, and notably halts the
onset of AKI. This remarkable finding is a major advance in this field that currently lacks any therapy to prevent or reverse septic AKI.
In this proposal we will develop clinically feasible strategies to avoid renal hypoxia and septic AKI. We have three aims: 1) To determine if in
established septic AKI, anti-oxidants can reverse medullary hypoxia and improve renal function. 2) To determine whether the beneficial effects of antioxidants depend on decreased oxidative stress and increased bioavailability of nitric oxide in the renal medulla. 3) To establish in sepsis if addition of an anti-oxidant to standard-of-care therapy (fluid + noradrenaline) or to a novel reno-protective therapy (fluid + angiotensin II) reduces the level of AKI and leads to more rapid recovery of renal function. We are in a unique position to establish the safety and efficacy of antioxidants in septic AKI, to determine the optimal dose and route of
administration, and to assess if there are any interactions between antioxidants and clinical resuscitation protocols, which is essential for the design of clinical trials.