Patients with end-stage renal disease (ESRD) that require long-term hemodialysis need a reliable vascular access. The arteriovenous (A-V) fistula with its long patency rate and low complication profile is usually the first choice for vascular access creation. However, numerous fistulae fail due to neointimal hyperplasia (NIH). Despite the widely appreciated magnitude of this problem, there is paucity of research investigating the mechanisms responsible for neointimal formation in A-V fistulae. We have recently published two studies that describe the cellular dynamics of neointimal formation in the fistula wall. We have obtained evidences for the role of local progenitor cells during the pathological remodeling of A-V fistulae. In this proposal, we have brought together a multidisciplinary team of investigators to prove at the basic and clinical translational levels that the secretion of stem cel factor by smooth muscle cells in response to hemodynamic stress induces the myofibroblastic differentiation of vascular progenitors to initiate neointimal formation. We will also prove that inhibition of SCF/c-Kit signaling is sufficient to decrease and probably prevent neointimal formation in the fistula wall. We will test our hypothesis in four specific aims and six independen experiments that will demonstrate: 1) the contribution of local progenitor cells (c-Kit+) to the development of neointima in A-V fistulae~ 2) that inhibition of c-Kit ameliorate NIH in a porcine model of fistula stenosis, and 3) the relationship between c-Kit+ cells and the patency of human A-V fistulae. We will blend advanced transgenic mouse models with fine microsurgical techniques to successfully achieve our goals in the first two aims of the proposal. We will quantify the number of vascular wall progenitor cells (c-Kit+ Sox2+) in vein tissues collected at two different time points during two-stage brachiobasilic fistula creation in a cohort of 200 ESRD patients. We will correlate the number of progenitor cells in the fistula wall with the 8-wks blood flow rate and primary unassisted patency. In conclusion, with the successful accomplishment of this proposal, we are paving the way for the design of new therapeutic strategies that may prevent A-V fistula failure and reduce vascular access complications.

Public Health Relevance

Patients with end-stage renal disease require the creation of a vascular access to secure hemodialysis. Despite all technological and pharmacological advances in hemodialysis, the narrowing of blood vessels that give access to the patient circulation remains a major complication. It is estimated that every year over $1 billion is expended in the maintenance of vascular access and its complication in the US alone. This study aims at identifying pathogenic cells and molecules responsible for the failure of the most common vascular access, the arteriovenous fistula. Outcomes from these studies may represent a breakthrough that will provide new therapeutic targets and strategies to improve vascular access dysfunction, reduce medical complications and ultimately, save lives.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Kusek, John W
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Martinez, Laisel; Duque, Juan C; Tabbara, Marwan et al. (2018) Fibrotic Venous Remodeling and Nonmaturation of Arteriovenous Fistulas. J Am Soc Nephrol 29:1030-1040
Duque, Juan C; Tabbara, Marwan; Martinez, Laisel et al. (2018) Similar degree of intimal hyperplasia in surgically detected stenotic and nonstenotic arteriovenous fistula segments: a preliminary report. Surgery 163:866-869
Duque, Juan C; Tabbara, Marwan; Martinez, Laisel et al. (2017) Dialysis Arteriovenous Fistula Failure and Angioplasty: Intimal Hyperplasia and Other Causes of Access Failure. Am J Kidney Dis 69:147-151
Vazquez-Padron, Roberto I; Allon, Michael (2016) New Insights into Dialysis Vascular Access: Impact of Preexisting Arterial and Venous Pathology on AVF and AVG Outcomes. Clin J Am Soc Nephrol 11:1495-503
Tabbara, Marwan; Duque, Juan C; Martinez, Laisel et al. (2016) Pre-existing and Postoperative Intimal Hyperplasia and Arteriovenous Fistula Outcomes. Am J Kidney Dis 68:455-64
Duque, Juan Camilo; Gomez, Camilo; Tabbara, Marwan et al. (2015) The impact of arteriovenous fistulae on the myocardium: the impact of creation and ligation in the transplant era. Semin Dial 28:305-10
Salman, Loay H (2015) How is arteriovenous fistula longevity best prolonged?: The role of surveillance. Semin Dial 28:33-4
Duque, Juan C; Martinez, Laisel; Mesa, Annia et al. (2015) CD4(+) lymphocytes improve venous blood flow in experimental arteriovenous fistulae. Surgery 158:529-36
Ding, Wen; Li, Jihe; Singh, Jayanti et al. (2015) miR-30e targets IGF2-regulated osteogenesis in bone marrow-derived mesenchymal stem cells, aortic smooth muscle cells, and ApoE-/- mice. Cardiovasc Res 106:131-42
Martinez, Laisel; Gomez, Camilo; Vazquez-Padron, Roberto I (2015) Age-related changes in monocytes exacerbate neointimal hyperplasia after vascular injury. Oncotarget 6:17054-64

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