#6078 MODULATION OF TRYPTOPHAN METABOLISM IN SEPSIS-INDUCED ACUTE KIDNEY INJURY (AKI): A NEW THERAPEUTIC APPROACH TO PREVENT NEUROCOGNITIVE IMPAIRMENT

Abstract

Abstract Background and Aims Partial recovery following AKI could lead to long-term consequences that predispose to chronic dysfunction and may also accelerate progression of neurocognitive impairment. In this scenario, a tight crosstalk between kidney and brain named “kidney-brain axis” seems to play a pivotal role leading to detrimental outcome for AKI patients. Notably, many studies suggest a high relationship between kidney damage and brain dysfunction (cognitive impairment, taste and olfactory dysfunction, peripheral nerve dysfunction) even after the resolution of AKI. Furthermore, patients who suffered AKI may afterward show a disturbance of arousal, also called “brain fog”. Although major advances have been made in our understanding of the pathophysiology of AKI and brain dysfunction, there are no available preventive and therapeutic strategies in this field. Recent findings have revealed remarkable link existing between dyslipidemia/low High-density lipoprotein (HDL) levels and Kynurenine pathway (KP) alterations that lead to the production of neuroactive metabolites such as kynurenine (KYN) and quinolinic acid (QA) in AKI setting. Method Sepsis-induced AKI (SI-AKI) was induced in a porcine model by intravenous infusion of a saline solution containing 300 μg/kg of LPS. After LPS injection, 12 animals were treated with different doses of recombinant HDL (rHDL) (20–40 mg/kg) (rHDL group), while 6 animals did not receive treatment (LPS group). Animals were sacrificed after 24h from the start of experimental procedure. Results Endotoxemic pigs developed oliguric AKI with increased tubular and glomerular damage and interstitial inflammatory infiltrate. We found that rHDL treatment significantly decreased the inflammatory process and tubular damage, preventing AKI, especially in the rHDL 40 mg/kg group. Then, we evaluated the Indolamine-2,3-dioxygenase 1 (IDO1) enzyme activation, which is the first and rate-limiting step of KP, upregulated during inflammation in both sera and brain tissue, and has been linked to cognitive dysfunction. In our model, LPS induced an increased activation of the IDO-1 gene expression at brain level in endotoxemic animals, meanwhile it appears to be reduced in both treated arms (p<0.005). Furthermore, sera from the rHDL group showed a significant reduction in IDO1 activity (KYN/Trp ratio) (p<0.05) and QA levels (p<0.005) compared with the LPS group. Moreover, a significant decrease of both systemic and brain IL-6 levels was observed after rHDL treatments. Conclusion Our preliminary data indicated that HDL-enhancing therapies may decrease the inflammatory response, the retention of waste products and neuroactive compounds, improving renal and cognitive function in SI-AKI.