Abstract
Introduction:
The arteriovenous fistula (AVF) is the lifeline for patients with end-stage kidney disease (ESKD) requiring hemodialysis therapy. The mechanism of “arterialization”, by which a vein transforms into an AVF after anastomosis, is one of the most understudied transformative processes in vascular biology despite the urgent need for new interventions to facilitate and accelerate fistula usability to improve the life of these patients.
Hypothesis:
Dysregulation of type VIII collagen biosynthesis increases the risk for failure in newly created AVFs
Methods and Results:
We first deciphered the transcriptional transformation of the pre-access vein after arterial anastomosis using paired venous samples from 38 CKD patients undergoing surgeries for two-stage AVF creation. A total of 3,637 transcripts were differentially expressed (DE) between veins and AVFs in pairwise analyses (log2FC ≥ 1 or ≤ -1, FDR <0.05). Gene set enrichment analyses revealed transcriptional activation of genes related to vasculature development, ECM remodeling, SMC migration, and endothelial cell (EC) proliferation and migration. Two hundred and eighty-four DE transcripts belonged to the matrisome family of genes. These included 20 collagens, 52 ECM glycoproteins, 10 proteoglycans, 58 ECM regulators, 27 ECM-affiliated proteins, 26 proteoglycan biosynthetic/modifying enzymes, and 91 secreted factors. Next, we sought to identify the changes in gene expression during the vein to AVF transformation that were relevant to maturation failure. Pairwise differential gene expression analyses conditional to outcome identified 102 DEGs in association with AVF failure (log2FC ≥ 1 or ≤ -1, FDR <0.05). Eight genes in this group increased more in AVFs that failed compared to those that matured. Accumulation of COL8A1 was confirmed around medial SMC by IHC. This finding was further validated using an independent tissue cohort, which demonstrated significantly higher collagen VIII deposition in stenotic areas from resected AVF fragments compared to adjacent non-stenotic tissues.
Conclusions:
Vascular accumulation of type VIII collagen in the AVF wall after anastomosis strongly increases the risk of failure.
