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CHEMOKINE THERAPY FOR CHRONIC RENAL FIBROSIS

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title
CHEMOKINE THERAPY FOR CHRONIC RENAL FIBROSIS
author
Bennington, DVM, PhD, Julie
abstract
Chronic kidney disease (CKD) is a common, progressive disease that afflicts both human and veterinary patients worldwide. According to the National Kidney Foundation and the International Renal Interest Society, CKD affects 10% of the human population worldwide and up to 50% of cats age 15 years or older. Irreversible tubulointerstitial fibrosis is the common final pathway leading to end stage renal disease (ESRD) in both human and veterinary patients, requiring either dialysis or renal transplantation. Pharmaceutical and dietary interventions are also implemented to manage comorbidities, increase longevity, and improve quality of life. With a marked shortage in kidneys available for transplantation, regenerative therapies using bioengineered tissues, stem cells, and vascular fractions have been developed and tested in preclinical animal models and clinical trials. While modestly effective, these regenerative therapies require advanced cell processing and tissue engineering capabilities not available in most clinical settings, and alternative approaches are needed. In our studies, we used a cell-signaling chemokine (CXCL12) that is produced by cells, stimulates tissue regeneration, and may be a promising alternative approach to treat renal fibrosis. Recombinant human CXCL12 is commercially available, inexpensive, and has been shown to reduce fibrosis in rodent models of CKD. As such, the goal of our studies was to test the safety, feasibility, and efficacy of ultrasound-guided intra-renal CXCL12 injection in cats with chronic renal fibrosis; first in a preclinical cat model of unilateral ischemia/reperfusion (I/R)-induced renal fibrosis; and then in a pilot study, in cats with early CKD. In a small, separate study, we also measured early changes in markers for collagen degradation and collagen cross linking to help unlock mechanism of action of our treatment injection in our preclinical model. Limitations, such as small sample size, precluded significant statistical analyses, but further studies are warranted. In conclusion, the results of these preclinical and pilot studies together show that intra-renal injection of CXCL12 may be a potential new therapy to treat early CKD in cats with a capability for widespread clinical use and future translational applications to humans.
subject
cat model of chronic renal fibrosis
chemokine CXCL12
histomorphometry of collagen fibers
ischemia/reperfusion injury
local intra-renal injection
tubulo-interstitial fibrosis
contributor
Williams, J. Koudy (committee chair)
Shively, Carol (committee member)
Almeida-Porada, Graҫa (committee member)
Badlani, Gopal (committee member)
Soker, Shay (committee member)
date
2021-06-03T08:35:56Z (accessioned)
2021-12-02T09:30:10Z (available)
2021 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2021-12-02 (terms)
identifier
http://hdl.handle.net/10339/98788 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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