Access to high blood flow rate for chronic hemodialysis (HD) is usually achieved by the creation of an arteriovenous (AV) access. While native AV fistulas have fewer complications once they become functional, up to 60% never develop into a functioning access. The AV grafts are more reliable early but are plagued later with hyperplasia at the graft-vessel anastomoses and up to 50% fail in the first year. If the incidence of stenosis can be decreased, the AV graft would be a better option for chronic HD. Regrettably, there are no established clinical treatments for the prevention of AV graft stenosis;therefore, effective therapies are urgently needed. Adipocytes release many peptides, including adiponectin (ADPN) which has beneficial vascular effects, such as decreasing the expression of cellular adhesion molecules and inflammatory cytokines. For example, hyperplasia increased markedly following vascular injury in ADPN knock-out mice versus wild-type mice, while the placement of subcutaneous adipose tissue (AT) near blood vessels has been shown to have protective effects against vascular injury. Thus, it is likely AT can be exploited to inhibit stenosis in AV grafts. The anti-diabetic glitazone drugs also have inhibitory effects on key processes that contribute to vascular stenosis, including inflammation and vascular smooth muscle cell (SMC) proliferation. Of particular relevance, glitazones also increase the expression of ADPN by AT. The glitazones are lipophilic and avidly partition into AT, which can therefore be considered an endogenous depot for the drug. Thus, this strategy will exploit the vasculo-protective properties of AT and its potential to serve as a depot for glitazones. Also, the vasculo- protective effects of glitazones, and their ability to promote the release of ADPN will be utilized. Autologous grafting of subcutaneous AT to repair soft-tissue defects is commonly used in plastic surgery. Hence, herein the strategy is to transplant autologous glitazone-loaded subcutaneous AT to the AV graft, as both a depot for local delivery of glitazones and as an endogenous factory for the glitazone-enhanced production of ADPN. There are two Specific Aims.
Aim 1 will optimize the mixture of porcine AT and glitazone in vitro in preparation for its use in animal studies. The conditioned media produced from cultured AT mixed with different concentrations of glitazone will be compared for their ability to inhibit SMC proliferation.
Aim 2 will transplant autologous glitazone-loaded subcutaneous AT to the perivascular space around the anastomoses of AV graft in a porcine model. The lumen area and blood flow rate in the AV graft will be used as efficacy outcomes as determined by magnetic resonance imaging. Wound healing will also be assessed as a safety outcome. This work proposes a very novel and simple means of drug and endogenous hormone delivery that should have very limited toxicity due to its localized nature and the use of native tissue. This technique may also improve fistula usability and has broad applicability to other vascular pathologies.

Public Health Relevance

Hemodialysis vascular accesses are surgically created sites, typically in the arms that are used to remove and replace blood during hemodialysis for patients with kidney failure. Unfortunately these accesses fail at a high rate due to cell overgrowth in the access site resulting in more surgeries, significantly increased risks of infection, and increased risk of death for patients. This work uses the transplant of the patient's own fat tissue mixed with a drug to target the release of drug and beneficial proteins to the access site that will inhibit cell overgrowth and hopefully improve the functioning lifespan of these accesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK092553-02
Application #
8331578
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Flessner, Michael Francis
Project Start
2011-09-20
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$224,250
Indirect Cost
$74,250
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112