Recombinant High-Density Lipoprotein Modulates Inflammatory Response and Renal Dysfunction in a Swine Model of Sepsis-Induced AKI
- AKI: Mechanisms - II
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
- 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
- Sallustio, Fabio, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
- Gesualdo, Loreto, Universita degli Studi di Bari Aldo Moro, Bari, Puglia, Italy
Sepsis is a severe and dysregulated inflammatory disease that often precedes the development of acute kidney injury (AKI) with consequent worsening outcome. Although clinical data demonstrate that high-density lipoprotein (HDL) levels drop in septic patients with a poor prognosis, little is known about the molecular basis of HDL’s role in systemic inflammation and renal function. Here we investigate whether the use of recombinant HDL, CER-001, is effective in reducing inflammation during sepsis and preventing AKI.
Sepsis was induced by intravenous infusion of a saline solution containing 300 μg/kg of LPS in a porcine model. The animals were randomized into three groups: LPS (endotoxemic pigs, n=6), CER-001(20mg/kg) (LPS pigs treated with a single dose of CER-001 20mg/kg; n=6), and CER-001(40mg/kg) (LPS pigs treated with two doses of CER001 at time 0 and 3 hours later; n=6). Animals were sacrificed after 24h from the start of experimental procedure.
We observed an increased survival rate in both CER-001 treated groups of pigs compared to the LPS group. Furthermore, LPS injection led to a time-dependent increase of IL-6 in endotoxemic animals with respect to basal condition (T0). CER-001 treatment was able to reverse LPS effects. In particular, the second infusion of CER-001 three hours after the first dose (T3) strongly reduced IL-6 serum levels back to basal level (LPS p <0.05).
Similarly, we found high levels of TNF-α, MCP-1, sVCAM-1, s-ICAM-1 and ox-LDL in endotoxemic pigs that were significantly decreased in both CER-001 treatment arms. CER001 preserved liver and renal parenchyma, decreasing pathological scores of renal tubular and glomerular injury. Thus, CER-001 treatment preserved renal physiology, recovering urine output and decreasing creatine levels.
Then, we evaluated the circulating LPS concentration in treated animals. We observed that LPS levels were greaty reduced in treated animals and the effects are more evident after the second infusion of CER-001. Therefore, we also examined LPS levels in bile samples and we observed a dose-dependent increasing amount of endotoxin in the CER001 treated pigs.
The nephroprotective regimens with CER-001 may be a promising therapeutic approach for future sepsis induced-AKI treatment.