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Abstract: FR-PO470

Uremia and a Lack of Krüppel-Like Factor-2 (KLF-2) Are Responsible for an Inadequate Positive (Outward) Venous Remodeling in a Mouse Model of Arteriovenous Fistula (AVF) Stenosis

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

  • Sidhu, Jasleen, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Lewis, Taylor G., The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Wai, Christine, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Jarrouj, Aous, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Saum, Keith Louis, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Celdran-Bonafonte, Diego, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Campos, Begoña, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Arteaga, Eyla C., The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Xi, Gang, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Uriyanghai, Unimunkh, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
  • Roy-Chaudhury, Prabir, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States
Background

Although AVFs remain the gold standard for dialysis vascular access they have a maturation failure rate of over 50% at 6 months post surgery due to a combination of neointimal hyperplasia and an inadequate positive (outward) remodeling. A central molecule in the mechanotransduction pathways responsible for outward remodeling in response to increased flow is KLF-2. In order to better understand the mechanisms of inadequate outward remodeling in AVF maturation failure we aim to describe the impact of both uremia and the absence of KLF-2 in our mouse model of AVF stenosis.

Methods

AVFs were created between the carotid artery and jugular vein in (a) non-uremic WT C57Bl/6 animals (b) uremic WT animals (c) non-uremic KLF-2 KO animals and (d) uremic KLF-2 KO animals (n=3 in each group). The degree of outward remodeling was assessed by measuring the change in the venous perimeter from the juxta-anastomotic segment (0 microns from the anastomosis) to proximal vein 1200 microns downstream (proximal) to the anastomosis, using Image J morphometry.

Results

Non-uremic WT animals had a 48% increase (p<0.0001) in venous perimeter across the length of the venous segment (from 0-1200 microns). In marked contrast both the KLF-2 KO animals and the uremic animals (regardless of KLF-2 presence or absence) completely lost this increase in venous perimeter (outward remodeling).

Conclusion

Our results demonstrate that KLF-2 is likely a strong driver of positive (outward) remodeling in our mouse model of AVF stenosis. At the same time uremia appears to be a strong inhibitor of outward remodeling (likely as a result of endothelial dysfunction) such that the presence or absence of KLF-2 in uremic animals does not have any impact on the remodeling process. Looking to the future our data suggest that (a) creating a local milieu around the AVF which inhibits the impact of uremic toxins and (b) upregulating KLF-2 are two molecular approaches that could reduce AVF maturation failure.

Funding

  • Private Foundation Support