CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Kokubo, Taku; Ishikawa, Noriyuki; Uchida, Hisashi; Chasnoff, Sara E.; Xie, Xiulan; Mathew, Suresh; Hruska, Keith A.; Choi, Eric T.

doi:10.1681/asn.2007121312

Cited by 106 publications

(111 citation statements)

References 41 publications

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“…The existence of stem cells in the fistula wall was recently suggested by Caplice et al (8), who described this type of cells as components of adventitial microvessels in the rat A-V fistula. A number of studies have proposed bone marrow-derived progenitor cells as the source of neointimal cells in stenotic blood vessels after arterial injury (38,44,46), but their contribution seems less pronounced in the case of venous hyperplasia, as clearly demonstrated in three independent studies (9,21,43). The present work highlights the critical role played by this pathway in A-V fistula remodeling.…”

Section: Discussionsupporting

confidence: 56%

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c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Skartsis

Martinez

Duque

et al. 2014

American Journal of Physiology-Renal Physiology

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Skartsis N, Martinez L, Duque JC, Tabbara M, Velazquez OC, Asif A, Andreopoulos F, Salman LH, Vazquez-Padron RI. c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae. Am J Physiol Renal Physiol 307: F1095-F1104, 2014. First published September 3, 2014 doi:10.1152/ajprenal.00292.2014.-Stenosis of arteriovenous (A-V) fistulae secondary to neointimal hyperplasia (NIH) compromises dialysis delivery, which worsens patients' quality of life and increases medical costs associated with the maintenance of vascular accesses. In the present study, we evaluated the role of the receptor tyrosine kinase c-Kit in A-V fistula neointima formation. Initially, c-Kit was found in the neointima and adventitia of human brachiobasilic fistulae, whereas it was barely detectable in control veins harvested at the time of access creation. Using the rat A-V fistula model to study venous vascular remodeling, we analyzed the spatial and temporal pattern of c-Kit expression in the fistula wall. Interestingly, c-Kit immunoreactivity increased with time after anastomosis, which concurred with the accumulation of cells in the venous intima. In addition, c-Kit expression in A-V fistulae was positively altered by chronic kidney failure conditions. Both blockade of c-Kit with imatinib mesylate (Gleevec) and inhibition of stem cell factor production with a specific short hairpin RNA prevented NIH in the outflow vein of experimental fistulae. In agreement with these data, impaired c-Kit activity compromised the development of NIH in A-V fistulae created in c-Kit W/Wv mutant mice. These results suggest that targeting of the c-Kit signaling pathway may be an effective approach to prevent postoperative NIH in A-V fistulae. arteriovenous fistula; hemodialysis; neointima THE ARTERIOVENOUS (A-V) fistula is the preferred type of vascular access for hemodialysis patients (29). It achieves higher patency rates, has fewer complications than synthetic grafts (12,29,31), and has a lower risk of infections than central venous catheters (17,29). Despite its advantages, A-V fistulae frequently fail to mature or become dysfunctional after successful dialysis sessions, and this occurs primarily due to the development of neointimal hyperplasia (NIH) within the A-V fistula circuit (2, 5, 39). Stenosed A-V fistulae can sometimes be salvaged through angioplasty or surgical interventions, but these attempts often result in restenosis or additional complications (32). Therefore, there is an unmet medical need for treatments that prevent NIH and improve A-V fistula function. To this end, it is necessary to better define the factors underlying the pathological remodeling of the A-V fistula wall.A-V fistula maturation is a dynamic vascular process with multiple factors contributing to the development of NIH. These include vein configuration (22) In the present study, we investigated the role of c-Kit in the pathological remodeling of A-V fistulae. We show that activation of the c-Kit signaling pathway in adventitial and neointimal cells precedes arteri...

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Section: Discussionsupporting

confidence: 56%

“…left common carotid artery to the external jugular vein, as previously reported (21). Venous sections were obtained 30 days after surgery and submitted for histopathological analysis.…”

Section: Blockade Of Either C-kit or Scf In Rat A-v Fistulae Effectivmentioning

confidence: 99%

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

Skartsis

Martinez

Duque

et al. 2014

American Journal of Physiology-Renal Physiology

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“…This present model does not incorporate the uremic milieu. Therefore, the incorporation of a model of chronic renal failure 17 would be a valuable additive step to further improve the validity of this murine model.…”

Section: Representative Resultsmentioning

confidence: 99%

A Novel Murine Model of Arteriovenous Fistula Failure: The Surgical Procedure in Detail

Wong

Vries

Wang

et al. 2016

JoVE

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The arteriovenous fistula (AVF) still suffers from a high number of failures caused by insufficient remodeling and intimal hyperplasia from which the exact pathophysiology remains unknown. In order to unravel the pathophysiology a murine model of AVF-failure was developed in which the configuration of the anastomosis resembles the preferred situation in the clinical setting. A model was described in which an AVF is created by connecting the venous end of the branch of the external jugular vein to the side of the common carotid artery using interrupted sutures. At a histological level, we observed progressive stenotic intimal lesions in the venous outflow tract that is also seen in failed human AVFs. Although this procedure can be technically challenging due to the small dimensions of the animal, we were able to achieve a surgical success rate of 97% after sufficient training. The key advantage of a murine model is the availability of transgenic animals. In view of the different proposed mechanisms that are responsible for AVF failure, disabling genes that might play a role in vascular remodeling can help us to unravel the complex pathophysiology of AVF failure. Video LinkThe video component of this article can be found at

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“…However, recently, several groups have created porcine (66) and murine (67) models of CKD to study dialysis access dysfunction. In a murine model with CKD, accelerated neointimal hyperplasia was present in AVFs compared with non-CKD mice (67). In addition to porcine and murine models of CKD to study vascular access dysfunction, a rat model of CKD has also been superimposed on the rat AVF to demonstrate the damaging effect of uremia on the AVF in rat (39).…”

Section: Future Perspectives: New Frontiers In Vascular Access Researmentioning

confidence: 99%

Novel Paradigms for Dialysis Vascular Access

Lee

2013

Clinical Journal of the American Society of Nephrology

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SummaryVascular access dysfunction is a major cause of morbidity and mortality in hemodialysis patients. The most common cause of vascular access dysfunction is venous stenosis from neointimal hyperplasia within the perianastomotic region of an arteriovenous fistula and at the graft-vein anastomosis of an arteriovenous graft. There have been few, if any, effective treatments for vascular access dysfunction because of the limited understanding of the pathophysiology of venous neointimal hyperplasia formation. This review will (1) describe the histopathologic features of hemodialysis access stenosis; (2) discuss novel concepts in the pathogenesis of neointimal hyperplasia development, focusing on downstream vascular biology; (3) highlight future novel therapies for treating downstream biology; and (4) discuss future research areas to improve our understanding of downstream biology and neointimal hyperplasia development.

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CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Cited by 106 publications

References 41 publications

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

c-Kit signaling determines neointimal hyperplasia in arteriovenous fistulae

A Novel Murine Model of Arteriovenous Fistula Failure: The Surgical Procedure in Detail

Novel Paradigms for Dialysis Vascular Access

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