Abstract: FR-OR041

Early Transcriptional Changes Associated with the Altered Flow Environment and Intimal Hyperplasia Following AVF Creation

Session Information

Category: Dialysis

  • 603 Hemodialysis: Vascular Access

Authors

  • Staton, Kyle M, The University of Florida, Gainesville, Florida, United States
  • Rozowsky, Jared, University of Florida, Gainesville, Florida, United States
  • Hu, Qiongyao, The University of Florida, Gainesville, Florida, United States
  • Barbey, Sarah, The University of Florida, Gainesville, Florida, United States
Background

While recent clinical studies have provided insights into factors that dictate success or failure in arteriovenous fistula (AVF) maturation, advances in our understanding of the fundamental biology within the fistula vein wall that controls these events has been limited to animal models. Two-stage basilic vein transposition (BVT) fistula offer the unique opportunity for collection of vein wall sample at initial placement and 4-6 weeks following AVF creation. This study utilizes high-throughput genomics to evaluate the transcriptional changes associated with the independent effects of vein wall pathology versus the altered flow environment on mRNA expression.

Methods

Vein samples were collected from patients at Stage 1 and Stage 2 of BVT creation (n=14). mRNA was isolated and analyzed for 44,699 genes using the HTA 2.0 microarray. BRB ArrayTools and Ingenity Pathway Analysis was used to identify genome changes, relevant ontologies, and upstream regulators. Histomorphometry was evaluated using Movat’s stain.

Results

Substantial heterogeneity was identified at the time of AVF creation (intimal thickness: range =42-260 μm; mean = 133 μm). 86% of the Stage 2 samples demonstrated an increase in intimal thickness from baseline, with 50% of these veins exhibiting a greater than 2-fold increase in intima. A linear mixed model demonstrated 150 genes associated with the stage of fistula creation and 51 genes associated with extent of intimal disease (>1.5-fold change, p<0.01; Figure). Genes regulating AVF creation/local flow environment were associated with cell cycle progression, metabolism, and inflammation (with IL1, IL12, and CCL4 as extracellular regulators). Genes related to the extent of intimal disease were related to cell migration, cell cycle progression, and cell death (with ADAMTS1, PDGF, and TGFβ as regulators).

Conclusion

Within the vein wall of patients undergoing AVF creation, independent genomic signatures related to alterations in flow and intimal hyperplasia can be identified. These differences offer the opportunity for development of target interventional strategies to improve AVF maturation and durability.

Funding

  • Other NIH Support