NEPTUNE — NEphroProtective Treatment Using Noticing Early perioperative distress
Does ketone supplementation protect the kidney during cardiac surgery by improving renal metabolism and medullary oxygenation? A three-year Veni fellowship carrying the question from stored blood samples, to an ovine model, to a clinical proof-of-concept trial.
The idea
Cardiac Surgery-Associated AKI converges on a common mechanistic bottleneck: disturbed renal medullary perfusion and hypoxia. Ketones — whether from supplementation, ketogenic diets, or SGLT2-inhibitor-induced ketogenesis — improve recovery from cardiac ischaemia, reduce oxidative stress, improve mitochondrial efficiency, and increase tissue oxygenation under hypoxia. In preclinical models, ketone infusion protects against ischaemia-reperfusion injury in the kidney, heart, liver, and brain. It has never been tested during cardiac surgery itself.
My own postdoctoral work found that SGLT2 inhibitors reduce postoperative AKI, and separately showed that ketogenesis rises during cardiac surgery and correlates with suppression of HIF-1α — consistent with the idea that SGLT2i renoprotection runs, at least partly, through ketones. (Full results of that trial are under journal embargo and will be added here once published.)
Three work packages
Metabolomic profiling
Uses bio-banked blood and urine samples from ~200 MERCURI-2 participants to map ketone metabolism, oxidative stress, and kidney-injury markers before and after surgery — identifying the metabolic signature of SGLT2i-associated renoprotection.
Mechanistic ovine model
With the Florey Institute (Melbourne), an established ovine model of sepsis-associated AKI tests high- and low-dose ketone (BHB/AcAc) infusion against placebo, measuring renal cortical and medullary oxygenation, perfusion, function, and tubular injury on histopathology — 8 sheep per group.
Clinical proof-of-concept
A double-blind, randomised trial in elective cardiac surgery patients (target ~128, 61/arm after drop-out): intravenous ketone infusion versus placebo from induction of anaesthesia until the end of surgery, with continuous urinary oxygenation (PuO2), contrast-enhanced renal ultrasound (CERUS), metabolomics, and AKI (KDIGO) to day 30.
Why it matters: if ketone supplementation protects the kidney the way SGLT2 inhibitors appear to, it opens a second, drug-independent route to renoprotection — relevant even for patients who can’t take SGLT2 inhibitors.
Where this leads
NEPTUNE shares its biological material with MERCURI-2 and its mechanistic focus complements STELLAR‘s long-term follow-up question — together, the three studies span mechanism, acute prevention, and long-term outcome.