Canagliflozin Mitigates Acute Kidney Injury Secondary to Resuscitative Endovascular Balloon Occlusion of the Aorta in a Porcine Model of Hemorrhagic Shock

Simon Tallowin; Biebele Abel; Brinda Mysore; John Mares; Joseph A Anderson; Brandon W Propper; Ian J Stewart; David M Burmeister

doi:10.1097/SLA.0000000000006501

Canagliflozin Mitigates Acute Kidney Injury Secondary to Resuscitative Endovascular Balloon Occlusion of the Aorta in a Porcine Model of Hemorrhagic Shock

Ann Surg. 2024 Aug 23. doi: 10.1097/SLA.0000000000006501. Online ahead of print.

Authors

Simon Tallowin^{1

2}, Biebele Abel¹, Brinda Mysore¹, John Mares¹, Joseph A Anderson³, Brandon W Propper^{1

4}, Ian J Stewart⁵, David M Burmeister^{1

5}

Affiliations

¹ Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
² Academic Department of Military Surgery and Trauma, Royal Centre for Defence Medicine, Birmingham, UK.
³ Department of Laboratory Animal Resources, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁴ Walter Reed National Military Medical Center, Bethesda, MD, USA.
⁵ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

PMID: 39176564
DOI: 10.1097/SLA.0000000000006501

Abstract

Objective: We investigated the potential of acute canagliflozin administration to mitigate acute kidney injury (AKI) and attenuate deleterious pro-inflammatory cytokine release in a clinically relevant swine model of severe renal ischemia reperfusion injury (IRI) induced by hemorrhage and aortic occlusion.

Background: Long-term canagliflozin use attenuates renal function decline and reduces AKI in diabetes mellitus and heart failure patients. Whilst several reports indicate prophylactic SGLT2 inhibition prevents AKI in IRI, the efficacy of acute administration on IRI and inflammation is not known.

Methods: Female swine (n=16) underwent controlled hemorrhage of 25% blood volume, followed by 90 min of aortic occlusion at the level of the renal ostia (via Resuscitative Endovascular Balloon Occlusion of the Aorta). A single 300 mg dose of oral canagliflozin or vehicle (saline) was delivered 5 mins into aortic occlusion. Hemodynamic monitoring, markers of renal function (serum creatinine, blood urea nitrogen, proteinuria and urinary neutrophil gelatinase-associated lipocalin) and serum cytokine concentrations (including interleukins: IL-1RA, IL-6, IL-8, IL-10, IL-18; and Tumor necrosis factor alpha) were analyzed after IRI, and during a 6h critical care phase.

Results: Compared to controls, animals receiving canagliflozin had less severe AKI, improved creatinine clearance, reduced proteinuria, and significantly lower tubular damage as evidenced by histopathology and urinary NGAL. Furthermore, the pro-inflammatory cytokine IL-6 was markedly attenuated without reduction in anti-inflammatory cytokines (IL-1RA and IL-10).

Conclusions: A single dose of canagliflozin administered shortly into ischemic insult mitigates AKI and attenuates harmful pro-inflammatory cytokine release following trauma or surgery. These findings suggest a potential novel therapeutic role for canagliflozin in mitigating the effects of renal IRI worthy of further investigation.