Abstract: FR-PO469
Levels of Interleukin 8 and Monocyte Chemoattractant Protein-1 Are Associated with Arteriovenous Fistula Events and Upregulated in the Endothelium by Indoxyl Sulfate and TGF-β Pathway
Session Information
- Dialysis: Vascular Access
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 803 Dialysis: Vascular Access
Authors
- Bataille, Stanislas, Institut Phocéen de Néphrologie, Clinique Bouchard, ELSAN, Marseille, France
- Chermiti, Rania, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
- Giaime, Philippe, Institut Phocéen de Néphrologie, Clinique Bouchard, ELSAN, Marseille, France
- Pedinielli, Nathalie, Institut Phocéen de Néphrologie, Clinique Bouchard, ELSAN, Marseille, France
- Mc kay, Nathalie, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
- Lano, Guillaume, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
- Tawfik, Addi, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
- Mancini, Julien, APHM, Hop Timone, Public Health Department (BIOSTIC), Marseille, France
- Burtey, Stephane, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
- Dou, Laetitia, C2VN, Aix-Marseille Université, INSERM, INRAE, Marseille, France
Background
Arteriovenous fistula (AVF) failure due to stenosis or acute thrombosis is a major concern in haemodialysis (HD) patients. Intimal hyperplasia responsible for AVF stenosis can be caused by several factors like endothelial dysfunction, uremic toxins, and inflammatory/profibrotic molecules. Studies suggest that endothelium-secreted inflammatory molecules Interleukin 8 (IL8) and Monocyte Chemoattractant Protein-1 (MCP-1) trigger intimal invasion of smooth muscle cells and enhance intimal thickening. We investigated the association of IL8 and MCP-1 serum levels with AVF events in haemodialysis patients and studied the ability of the uremic toxin indoxyl sulfate to upregulate IL8 and MCP-1 expression in endothelial cells.
Methods
We conducted a retrospective observational study in 205 haemodialysis patients with AVF. In vitro, we studied the mRNA expression of IL8 and MCP-1 in endothelial cells incubated with indoxyl sulfate at uremic concentration (200µM).
Results
During the study period of 731 days, 64 patients had an AVF event defined as a composite of the first occurrence of AVF thrombosis or AVF stenosis requiring endovascular treatment. Kaplan-Meier analysis revealed that patients with serum levels of IL8 > 0 pg/ml or MCP-1> 720 pg/ml had significantly more AVF events. Serum levels of IL8 and MCP-1 were positively correlated with the levels of the pro-fibrotic molecule TGFβ1 in HD patients. In addition, serum levels of MCP-1 were positively correlated with indoxyl sulfate. In vitro, indoxyl sulfate upregulated endothelial expression of IL8 and MCP-1 by activating its receptor, aryl hydrocarbon receptor, which in turn activated the non-canonical TGFβ pathway involving TAK1, p38 MAPK, and the transcription factor AP-1. The stimulation of the TGFβ signalling pathway by TGFβ1 amplified indoxyl sulfate-mediated IL8 and MCP-1 expression.
Conclusion
We demonstrated that AVF events are associated with high serum levels of IL8 and MCP-1, which are upregulated in the endothelium by activation of the TGFβ non-canonical pathway by the uremic toxin indoxyl sulfate. Our study could provide therapeutic targets to limit intimal hyperplasia and prevent AVF events in haemodialysis patients.
Funding
- Private Foundation Support