Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce chronic kidney disease progression in people with type 2 diabetes mellitus. Sepsis is the leading cause of acute kidney injury (AKI). This study investigated whether GLP-1 is renoprotective in an ovine model of gram-negative septic AKI. Sixteen healthy merino ewes were surgically instrumented to measure mean arterial pressure, cardiac output, renal blood flow, renal cortical and medullary perfusion and oxygenation, and renal function. After a 5-day recovery period, sepsis was induced via continuous intravenous infusion of live Escherichia coli for 30 h. After 24 h, the sheep were randomized to receive an intravenous infusion of 3.6 pmol/kg/min GLP-1 (n = 8) or a fluid-matched vehicle (n = 8) for 6 h. After 24 h of sepsis, 7/8 sheep in each group developed AKI. GLP-1 treatment increased renal blood flow compared to placebo + 13 vs. - 3.4 ml/min difference (95% CI) = 16 (- 7-40) P = 0.0054), and maintained renal cortical oxygenation + 2.5 mmHg vs. = - 7.2 mmHg, difference (95% CI) = 9.7 (5.2-14.4) P < 0.001. GLP-1 maintained renal medullary perfusion + 1.7 vs. vehicle - 213 perfusion units, difference (95% CI) = 214 (- 21-450) P = 0.07. However, GLP-1 did not significantly improve the primary endpoint of renal medullary oxygenation - 1.6 vs. - 11.5, difference (95% CI) = 9.9 (- 6.8-26.7) P = 0.21. In an ovine model of gram-negative sepsis-associated AKI, GLP-1 infusion supported global renal perfusion, renal oxygen delivery, and cortical oxygenation but failed to improve renal medullary oxygenation and kidney function.