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

Objective: – To investigate 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. While 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 (through 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 (ILs): IL-1RA, IL-6, IL-8, IL-10, IL-18, and tumor necrosis factor–alpha] were analyzed after IRI, and during a 6-hour critical care phase. Results: – Compared with controls, animals receiving canagliflozin had less severe AKI, improved creatinine clearance, reduced proteinuria, and significantly lower tubular damage as evidenced by histopathology and urinary neutrophil gelatinase-associated lipocalin (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 after controlled hemorrhage in a swine model. These findings suggest a potential novel therapeutic role for canagliflozin in mitigating the effects of renal IRI worthy of further investigation.