Abstract 15088: Anti-Thrombin Nanoparticles Minimize Kidney Ischemia-Reperfusion Injury by Reducing Inflammation and Preserving Vascular Integrity

Introduction:Acute kidney injury (AKI) confers a 25% chance of developing chronic kidney disease and a 50% increase in 10-year mortality risk. Clinical trials completed in 2018 indicated that targeting single pathological mechanisms of AKI failed to improve renal function and overall outcomes.Hypothesis:We hypothesized that local thrombin inhibition with sustained acting nanoparticle formulations would both protect renal vasculature and modulate inflammatory prostaglandins that drive the ischemia reperfusion injury (IRI) process even when administered after onset of injury.Methods:23 male C57Bl6 mice underwent bilateral warm IRI. Two hours after reperfusion, the mice were injected with either anti-thrombin (PPACK: phenylalanine-proline-arginine chloromethylketone) or control perfluorocarbon NPs. After 24 hours, kidneys were harvested for histological analyses and inflammatory prostaglandins by HPLC-MS, and blood for BUN.Results:PPACK NP treatment preserved renal vasculature (more purple CD31 stain in A vs B), reduced vascular inflammation (less VCAM-1 glomerular staining in C vs D), and preserved basement membrane and brush border components (intact peri-glomerular PAS staining in E vs F). Renal function was improved at 24 hours (G). PGD2 was reduced in both cortex and medulla (H and I).Conclusion:Targeting thrombin preserves renal vasculature and reduces inflammation, which improves renal function well after the onset of renal IRI induced AKI.Figure. Anti-thrombin nanoparticle treatment 2 hours after onset of AKI