Abstract: TH-PO0123
Targeting Kynurenine Pathway Dysregulation in Sepsis-Induced AKI: Novel HDL-Based Strategy to Prevent Neurocognitive Decline
Session Information
- AKI: Mechanisms - 1
November 06, 2025 | Location: Exhibit Hall, 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, Apulia, Italy
- Stasi, Alessandra, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Fiorentino, Marco, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Franzin, Rossana, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Staffieri, Francesco, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Crovace, Alberto Maria, Universita degli Studi di Sassari, Sassari, Sardinia, Italy
- Cibelli, Antonio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Barile, Barbara, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Campioni, Monica, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Carparelli, Sabrina, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Sallustio, Fabio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Pontrelli, Paola, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Nicchia, Grazia Paola, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Crovace, Antonio, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
- Keyserling-Peyrottes, Constance, Abionyx Pharma SA, Balma, Occitanie, France
- Tupin, Cyrille, Abionyx Pharma SA, Balma, Occitanie, France
- Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Apulia, Italy
Background
Cognitive impairment following acute kidney injury (AKI), particularly in the context of sepsis, underscores the urgent need for targeted neuroprotective therapies. We investigated the efficacy of CER-001, an engineered HDL-mimetic, in modulating the kynurenine pathway (KP), a key source of neuroactive and neurotoxic metabolites, within a translational framework comprising both a swine model of SI-AKI and a Phase 2a clinical trial.
Methods
SI-AKI was induced in 18 swine via intravenous infusion of LPS. Twelve animals received CER-001 at either 20 mg/kg or 2×20 mg/kg, while six served as untreated controls (LPS group). Serum levels of kynurenine (KYN), kynurenic acid (KYNA), quinolinic acid (QA), tryptophan (Trp), and serotonin (5-HT), were quantified by ELISA. At 24 hours, brain tissue was collected for transcript and protein analysis. Transcytosis across the blood-brain barrier, was assessed via scavenger receptor class B type I (SR-B1) expression. In parallel, 20 septic patients were enrolled in a Phase 2a trial: 5 received standard care, while 15 were treated with CER-001. KP biomarkers were analyzed longitudinally.
Results
In treated swine, CER-001 significantly downregulated Indoleamine 2,3-dioxygenase (IDO1) (p<0.005) and upregulated aromatic L-amino acid decarboxylase (p<0.0005), favoring 5-HT synthesis and reducing QA levels, KYN/Trp and QA/KYNA ratios.
CER-001 also decreased glial activation markers Glial Fibrillary Acidic Protein and Connexin 43 (p<0.05) while enhancing SR-B1 expression (p<0.05), supporting improved HDL-mediated BBB transport. In the clinical setting, CER-001-treated patients exhibited reduced QA values, KYN/Trp ratio, and increased 5-HT levels.
Conclusion
These findings support CER-001 as a promising therapeutic to counteract neuroinflammation and preserve cognitive function in SI-AKI by reprogramming KP metabolism, attenuating astrocyte reactivity, and enhancing HDL-mediated neuroprotective signaling.