# Integrin Activation to Prevent Early Arteriovenous Fistula Failure in End-stage Renal Disease Patients

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $557,622

## Abstract

The autogenous arteriovenous (A-V) fistula represents the most important lifeline of >600,000 Americans
currently on hemodialysis. However, ~40 percent of newly created fistulas cannot be used for dialysis
without a salvage procedure because stenosis (narrowing) prevents them from reaching the necessary
blood flow. This problem represents significant comorbidity for the end-stage renal disease (ESRD)
population and a substantial economic burden that currently surpasses $2 billion annually. Most troubling
about this glaring statistic is that it has plateaued over the past five decades, highlighting a pressing need for
revamped efforts to improve vascular access outcomes using novel and innovative therapeutic approaches.
This translational proposal establishes a new modality to treat post-operative A-V fistula failure using an
emerging anti-inflammatory concept. We have built this proposal upon the premise that a newly discovered
agonist of Mac-1 integrin prevents stenosis in A-V fistulas by controlling post-operative inflammatory activity.
Macrophages and other myeloid inflammatory cells control the underlying causes of stenosis, such as the
development of post-operative intimal hyperplasia (IH) and fibrosis. Herein we hypothesize that
pharmacological and genetic activation of the Mac-1 integrin is sufficient to control myeloid- derived
inflammatory cell infiltration in the fistula without compromising access maturation. We also hypothesize
that activation of the Mac-1 integrin attenuates the RAGE signaling in macrophages that leads to inward
remodeling in newly created A-V fistulas. Our scientific premise is supported by published and preliminary
data that demonstrate our experience with animal models to study fistula maturation biology. We will test our
hypothesis in three specific aims and five experimental layouts to: 1) demonstrate that increased monocyte
adhesion following Mac-1 activation protects experimental A-V fistulas from failure; 2) demonstrate the anti-
inflammatory mechanism following Mac-1 activation in the fistula wall; and 3) demonstrate that Mac-1
activation attenuates post-operative inflammation, IH, and stenosis in preclinical A-V fistulas. We will
combine fine microsurgical techniques and transgenic mice to achieve our goals successfully. In conclusion,
successful completion of this proposal will pave the way to the design of new drugs using a novel mode of
action to effectively target A-V fistula fibrosis and IH and reduce vascular access complications.

## Key facts

- **NIH application ID:** 10824698
- **Project number:** 1R01DK136297-01A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** VINEET GUPTA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $557,622
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824698

## Citation

> US National Institutes of Health, RePORTER application 10824698, Integrin Activation to Prevent Early Arteriovenous Fistula Failure in End-stage Renal Disease Patients (1R01DK136297-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10824698. Licensed CC0.

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