Transcriptomics of Human Arteriovenous Fistula Failure: Genes Associated With Nonmaturation

Rationale & Objective: Improving arteriovenous fistula (AVF) outcomes requires better understanding of the biology underlying maturation or failure. Our current knowledge of maturation relies on extrapolation from other vascular pathologies, which does not incorporate unique aspects of AVF remodeling. This study compares the RNA expression of pre-access (native) veins and AVFs with distinct maturation outcomes. Study Design: Case-control study. Setting & Participants: 64 patients undergoing 2-stage AVF surgeries at a single center. 19 native veins and 19 AVF samples were analyzed using RNA sequencing (RNA-seq). 58 native veins were studied using real-time polymerase chain reaction; 45, using immunohistochemistry; and 19, using Western blot analysis. Predictor: RNA expression in native veins and AVFs. Outcome: Anatomic nonmaturation, defined as an AVF that never achieved an internal diameter ≥ 6 mm. Analytical Approach: Pre-access native veins and AVF samples were obtained from patients undergoing 2-stage AVF creation. Veins that subsequently matured or failed after access creation were analyzed using RNA-seq to search for genes associated with maturation failure. Genes associated with nonmaturation were confirmed using real-time polymerase chain reaction, immunohistochemistry, and Western blot analysis. In addition, the association between pre-access gene expression and postoperative morphology was evaluated. RNA-seq was also performed on AVFs to search for transcriptional differences between AVFs that matured and those that failed at the time of transposition. Results: Pro-inflammatory genes (CSF3R, FPR1, S100A8, S100A9, and VNN2) were upregulated in pre-access veins that failed (false discovery rate < 0.05), and their expression colocalized to smooth muscle cells. Expression of S100A8 and S100A9 correlated with postoperative intimal hyperplasia and the product of medial fibrosis and intimal hyperplasia (r = 0.32-0.38; P < 0.05). AVFs that matured or failed were transcriptionally similar at the time of transposition. Limitations: Small sample size, analysis of only upper-arm veins and transposed fistulas. Conclusions: Increased expression of proinflammatory genes in pre-access veins appears to be associated with greater risk for AVF nonmaturation.