# Adaptive immunity regulates arteriovenous fistula remodeling

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $760,763

## Abstract

The preferred vascular access for hemodialysis to treat end-stage renal disease involves using a vein
as a conduit to increase blood flow by surgically creating an arteriovenous fistula (AVF). Successful adaptation
of a venous conduit to the fistula or arterial environment requires remodeling of the vein wall without excessive
wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall
with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in
women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the
biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This
knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby to
increase successful clinical use of venous conduits.
 Using a mouse AVF model that recapitulates human AVF maturation and shows sex differences, we
have shown that both an innate immune response as well as an adaptive immune response regulate venous
remodeling. We present exciting new data that sex hormones mediate sex differences in wall thickness during
venous remodeling. In addition, we have developed the mouse model further to incorporate chronic kidney
disease (CKD) via 5/6-nephrectomy; AVF in the CKD environment show altered venous remodeling compared
with control mice and these AVF faithfully recapitulate human AVF maturation. We hypothesize that since T
cells mediate venous remodeling, modulating adaptive immunity will alter venous remodeling, thereby
improving AVF patency and ultimately fistula utilization in human patients. We will use our translationally
relevant in vivo model, an innovative tool encapsulating cyclosporine in nanoparticles for local drug delivery,
innovative methodology to analyze the immune cell composition within the AVF wall, as well as advanced next-
generation analyses using transcriptomics techniques that are available at Yale, to test our innovative
hypothesis with the following specific aims:
Aim I: Determine whether sex differences in adaptive immunity between women and men affect AVF
remodeling in vivo. Aim II: Determine whether sex hormones mediate sex differences in the immune response
during AVF remodeling in mice with CKD. Aim III: Determine whether PD-L1 expression regulates the effects
of adaptive immunity on AVF remodeling in mice with CKD.
 A successful outcome of this investigation will have lasting impact by establishing whether there is a T
cell basis underlying venous remodeling and thus manipulation of adaptive immunity is a valuable strategy for
clinical translation to enhance AVF patency. We will also determine whether reduced AVF maturation in
women is due to sex differences in adaptive immunity. We use an innovative strategy and novel tools and
models to manipulate adaptive immunity to alter venous remodeling and thereby improve AVF patency.

## Key facts

- **NIH application ID:** 10752672
- **Project number:** 5R01HL162580-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alan Dardik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $760,763
- **Award type:** 5
- **Project period:** 2022-12-12 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752672

## Citation

> US National Institutes of Health, RePORTER application 10752672, Adaptive immunity regulates arteriovenous fistula remodeling (5R01HL162580-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10752672. Licensed CC0.

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