Kidney Week

Abstract: FR-PO471

Local Sirolimus Delivery Reduces Arteriovenous Graft (AVG) Stenosis in a Pig Model

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

• Sudarsanam, Vinay A., The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Vinay A. Sudarsanam,

• Wai, Christine, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Christine Wai,

• Sidhu, Jasleen, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Jasleen Sidhu,

• Celdran-Bonafonte, Diego, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Diego Celdran-Bonafonte,

• Arteaga, Eyla C., The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Eyla C. Arteaga,

• Xi, Gang, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Gang Xi,

• Roy-Chaudhury, Prabir, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Prabir Roy-Chaudhury,

• Shebuski, Ron, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Ron Shebuski,

• Uriyanghai, Unimunkh, The University of North Carolina at Chapel Hill Kidney Center, Chapel Hill, North Carolina, United States

Unimunkh Uriyanghai,

Background

Dialysis vascular access is currently the “Achilles Heel” of hemodialysis due to the high rate of stenosis in both arteriovenous fistulae and arteriovenous grafts (AVG). AVG stenosis is due to an aggressive venous neointimal hyperplasia (NH) at the graft-vein anastomosis (GVA). Sirolimus is an anti-proliferative agent which has been shown to reduce NH in the setting of coronary stenting. We have previously developed a local sirolimus (SRL) drug eluting cuff (DEC; 2mg/month) linked to an osmotic pump that can be used to deliver high concentrations of SRL to the GVA with minimal systemic SRL exposure. We herein report on the use of the Sirolimus DEC (SDEC) versus a control solution (CDEC) in the setting of a validated pig model of AVG stenosis.

Methods

10 AVGs (6 SDEC and 4 CDEC) were created unilaterally in Yorkshire Cross pigs. Animals underwent weekly ultrasound assessments for patency and were sacrificed at 8 weeks post surgery. At the time of sacrifice 1cm of graft downstream to the DEC and 1.5cm of downstream (proximal vein) was collected for analysis of average (avg) and maximal (max) stenosis (including any attached thrombus) across the entire graft-vein segment and also within the individual vein and graft segments, using Image J.

Results

All 10 grafts were patent at the 56 day time point. Systemic SRL levels peaked at between 0.86 and 1.6ng/ml at 3d. Percentage avg. stenosis (SDEC=30.4% vs CDEC=50.8%; p=0.025) and max. stenosis (SDEC=60.1% vs CDEC=80.6%; p=0.02) across the entire graft-vein segment was significantly reduced in the SDEC group. A similar pattern was found in the venous segment for avg. stenosis (SDEC=46.4% vs CDEC=72.9%;p=0.01) and maximal stenosis (SDEC=60.1% vs CDEC=80.6%; p=0.02) but not in the graft only segment for either avg. (SDEC=6.6% vs CDEC=22.7%;p=0.13) or max. stenosis (SDEC=9.9% vs CDEC=27.4%;p=0.19).

Conclusion

Our results (a) demonstrate the technical feasibility of using a SDEC for the local delivery of SRL to the GVA (b) document minimal systemic SRL exposure due to the SDEC device and (c) describe a significant reduction in both avg. and max. stenosis across the entire graft-vein segment. Future clinical development of the SDEC could significantly reduce AVG stenosis and make AVGs the preferred modality for dialysis vascular access.

Funding

• Other NIH Support