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Kidney Week

Abstract: FR-PO181

Tryptophan Metabolism in AKI: A New Target in Kidney-Brain Axis

Session Information

  • AKI: Mechanisms - II
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Cimmarusti, Maria Teresa, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Stasi, Alessandra, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Franzin, Rossana, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Fiorentino, Marco, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Staffieri, Francesco, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Crovace, Alberto Maria, Universita degli Studi di Sassari, Sassari, Sardegna, Italy
  • Campioni, Monica, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Sallustio, Fabio, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Pontrelli, Paola, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Crovace, Antonio, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
  • Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
Background

Partial recovery following AKI could lead to long-term consequences that predispose to chronic dysfunction and may also accelerate neurocognitive decline. Kidney-brain axis seems to play a pivotal role leading to detrimental outcome for AKI patients. Many studies suggest a high relationship between kidney damage and brain dysfunction even after AKI resolution. Patients who suffered AKI may afterward show a disturbance of arousal called brain-fog. Although advances in understanding the pathophysiology of AKI and brain dysfunction, there are no available preventive and therapeutic strategies. Recent findings have revealed link existing between dyslipidemia/low HDL levels and Kynurenine pathway (KP) alterations that lead to the production of neuroactive metabolites: kynurenine (KYN) and quinolinic acid (QA).

Methods

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 injection, 12 animals were treated with different doses of recombinant HDL (rHDL) (20-40mg/kg), 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. rHDL treatment decreased the inflammatory process and tubular damage, preventing AKI, especially in 40mg/kg rHDL group. The rate-limiting step of KP, the Indolamine-2,3-dioxygenase 1 (IDO1) enzyme is upregulated during inflammation in sera and brain tissue, and has been linked to cognitive dysfunction. In our model, LPS induced an increased activation of IDO-1 gene expression at brain level in endotoxemic animals, meanwhile it appears to be reduced in both treated arms (p<0.005). 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 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.