Kidney Week

Abstract: TH-PO064

Brain-Kidney Interplay during Sepsis-Associated AKI: Results from the RACERS Study

Session Information

• AKI: Clinical, Outcomes, and Trials - Epidemiology and Pathophysiology
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 102 AKI: Clinical, Outcomes, and Trials

Authors

• Fiorentino, Marco, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Marco Fiorentino, MD

• Cimmarusti, Maria Teresa, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Maria Teresa Cimmarusti

• Stasi, Alessandra, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Alessandra Stasi, PhD

• Franzin, Rossana, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Rossana Franzin, PhD

• Carparelli, Sabrina, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Sabrina Carparelli, MD

• Campioni, Monica, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Monica Campioni, MSc

• Losapio, Rosa, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Rosa Losapio, MSc

• Caggiano, Gianvito, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Gianvito Caggiano, PhD

• Pontrelli, Paola, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Paola Pontrelli, PhD

• Keyserling-Peyrottes, Constance, Abionyx Pharma, Toulouse, France

Constance Keyserling-Peyrottes, ScM

• Tupin, Cyrille, Abionyx Pharma, Toulouse, France

Cyrille Tupin, PA, CPA

• Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy

Loreto Gesualdo, DrMed

Background

Recent preclinical studies have revealed a strong association between low levels of HDL and dysregulation of the kynurenine pathway (KP) in sepsis-associated AKI and cognitive dysfunction. In our preclinical model, treatment with a new engineered HDL (CER-001) downregulated the Indolamine-2,3-dioxygenase 1 (IDO1) enzyme, a crucial mediator of KP, by reducing kynurenine/tryptophan (KYN/Trp) ratio and quinolinic acid (QA) levels. We aim to analyze the effects of treatment in mitigating brain dysfunction in a Phase 2a clinical trial.

Methods

We performed a randomized Phase 2a study (RACERS study) including 20 patients with Gram negative sepsis, randomized to receive CER-001 (twice a day on Days 1, 2, 3 and 6) or standard of care (SOC) only. We analyzed the activity of KP between patients treated with CER-001 and SOC groups, by reporting changes from baseline of specific neuroactive metabolites such as KYN, KYN/Trp ratio, kynurenic acid (KYNA), QA and serotonin values.

Results

CER-001 treatment significantly reduced bloodstream concentrations of LPS, pro-inflammatory cytokines and circulating s-VCAM-1 and s-ICAM-1. Patients presenting with AKI at enrollment presented a tendence to higher values of KYN/Trp ratio (0.22, IQR 0.12-0.46) compared to patients without any stage of AKI at enrollment (0.12, IQR 0.07-0.28). CER-001 treatment reduced QA, KYN values and KYN/Trp ratio, suggesting the downregulation of IDO1, thus reducing the production of potential neurotoxic metabolites (Figure 1). We showed increased levels of tryptophan and the neuroprotective KYNA during treatment course, as well as a slight increase in serotonin, supporting the different regulation of tryptophan metabolism leading to neuroprotection.

Conclusion

CER-001 treatment downregulated IDO1 and reduce neuroactive metabolites and waste accumulation.

Effects of CER-001 on the kynurenine pathway in the RACERS study

Funding

• Commercial Support – Abionyx Pharma