Abstract: FR-PO507
Single-Cell Determinants of Hemodialysis Fistula Failure
Session Information
- Dialysis Vascular Access
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Dialysis
- 803 Dialysis: Vascular Access
Authors
- Martinez, Laisel, University of Miami Miller School of Medicine, Miami, Florida, United States
- Tabbara, Marwan, University of Miami Miller School of Medicine, Miami, Florida, United States
- Stoyell-Conti, Filipe F., University of Miami Miller School of Medicine, Miami, Florida, United States
- Rojas, Miguel G., University of Miami Miller School of Medicine, Miami, Florida, United States
- Pereira-Simon, Simone, University of Miami Miller School of Medicine, Miami, Florida, United States
- Vazquez-Padron, Roberto I., University of Miami Miller School of Medicine, Miami, Florida, United States
Background
Approximately half of newly created AVFs fail to mature without intervention. Despite this glaring statistic, all efforts to improve maturation have been unsuccessful due to our limited understanding of the venous adaptive response to arterial circulation. Our work presents a comprehensive cellular atlas of veins in ESKD patients before and after anastomosis, with a focus on molecular processes associated with failure.
Methods
We performed single-cell transcriptomic analyses on 70,281 cells obtained from 20 subjects on three different occasions: before anastomosis (n=6), one week after (n=2), and during transposition or revision of second-stage fistulas (n=6 matured, n=6 failed). Unsupervised clustering and gene expression analyses revealed the transcriptomic signature of AVF failure.
Results
The most abundant cells in pre-access veins and AVFs were endothelial cells (EC), fibroblasts, monocyte/macrophages, and NK/T cells. Gene expression profiles uncovered >1,000 differentially expressed genes (DEG) between pre-access veins and early AVFs in most cell clusters. Inflammation, not proliferation, dominated the initial transformation of vascular cells after anastomosis, a phenotype that prevailed in AVFs with unsuccessful maturation. Infiltrated monocytes were the primary source of wall cytokines dominating vascular remodeling. Immunofluorescence further confirmed the higher abundance of macrophages in failed vs. mature AVFs. Sub-clustering analyses discovered two new types of postoperative ECs, expressing hemostasis/shear stress factors or extracellular matrix genes, and a new population of fibroblasts characterized by upregulation of chemokine genes. The number of DEGs between mature and failed AVFs per cluster was less than one-tenth the one observed in the former comparison indicating that most transcriptional changes occur in the first week of remodeling. Upregulation of COL8A1 in ECs and myofibroblasts was associated with failure, identifying the cell sources for this previously validated failure-associated risk factor.
Conclusion
We uncovered the early and late adaptive response of the human vein after anastomosis at the single-cell resolution. We highlight the essential roles of postoperative EC populations, fibroblasts, and macrophages in orchestrating the reparative response of the vein to secure hemostasis and maturation.
Funding
- NIDDK Support