Challenges in Developing New Therapies for Vascular Access Dysfunction

Nath, Karl A.; Allon, Michael

doi:10.2215/cjn.06650617

Cited by 8 publications

(8 citation statements)

References 11 publications

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“…3 Despite the widespread recognition of a need for higher primary AVF patency rates, no clinically established pharmacologic or perisurgical therapies currently address this unmet need. 4 Therefore, further understanding of the mechanisms of AVF failure and development of new clinical strategies to reduce AVF failure hold vital interest for the dialysis community.…”

mentioning

confidence: 99%

Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula

Cui

Kessinger

Jhajj

et al. 2020

JASN

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BackgroundArteriovenous fistulas placed surgically for dialysis vascular access have a high primary failure rate resulting from excessive inward remodeling, medial fibrosis, and thrombosis. No clinically established pharmacologic or perisurgical therapies currently address this unmet need. Statins’ induction of multiple anti-inflammatory and antithrombotic effects suggests that these drugs might reduce arteriovenous fistula failure. Yet, the in vivo physiologic and molecular effects of statins on fistula patency and maturation remain poorly understood.MethodsWe randomized 108 C57Bl/6J mice to receive daily atorvastatin 1.14 mg/kg or PBS (control) starting 7 days before end-to-side carotid artery–jugular vein fistula creation and for up to 42 days after fistula creation. We then assessed longitudinally the effects of statin therapy on primary murine fistula patency and maturation. We concomitantly analyzed the in vivo arteriovenous fistula thrombogenic and inflammatory macrophage response to statin therapy, using the fibrin-targeted, near-infrared fluorescence molecular imaging agent FTP11-CyAm7 and dextranated, macrophage-avid nanoparticles CLIO-VT680.ResultsIn vivo molecular-structural imaging demonstrated that atorvastatin significantly reduced fibrin deposition at day 7 and macrophage accumulation at days 7 and 14, findings supported by histopathologic and gene-expression analyses. Structurally, atorvastatin promoted favorable venous limb outward remodeling, preserved arteriovenous fistula blood flow, and prolonged primary arteriovenous fistula patency through day 42 (P<0.05 versus control for all measures).ConclusionsThese findings provide new in vivo evidence that statins improve experimental arteriovenous fistula patency and maturation, indicating that additional clinical evaluation of statin therapy in patients on dialysis undergoing arteriovenous fistula placement is warranted.

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mentioning

confidence: 99%

Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula

Cui

Kessinger

Jhajj

et al. 2020

JASN

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“…2 Although vascular access dysfunction is considered a major health and economic burden, there are several challenges to optimizing vascular access outcomes or understanding the pathophysiology of access thrombosis. 3,4 On the other hand, axillo-femoral bypass has been traditionally used as an alternative approach in high-risk patients with aorto-iliac occlusive disease, in abdominal graft infections and in patients with “hostile” abdomen. 5 Since the advent of endovascular therapy, these extra-anatomic bypasses have largely been replaced by minimally invasive options such as balloon angioplasty, stenting, and atherectomy devices.…”

Section: Commentmentioning

confidence: 99%

Use of a temporary shunt to preserve the patency of a hemodialysis graft while performing ipsilateral axillo-femoral bypass

et al. 2019

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Increased blood flow in the subclavian artery feeding a vascular access for hemodialysis can rarely induce steal phenomena in the vertebral and internal mammary artery leading to potentially life-threatening conditions. On the contrary, transient interruption of blood flow in the subclavian artery feeding a dialysis arteriovenous fistula can theoretically induce access thrombosis. Here, we describe a technical maneuver preserving continuous ipsilateral upper arm access flow when constructing a unilateral axillo-femoral polytetrafluoroethylene bypass operation for critical limb ischemia in a hemodialysis patient.

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“…A functional vascular access is critical for effective hemodialysis. AV fistula dysfunction largely reflects maturational failure, whereas AV graft dysfunction is mainly driven by recurrent stenosis and thrombosis in the venous anastomosis [9]. The current understanding of the biology of vascular access dysfunction remains inadequate and problematic.…”

Section: Introductionmentioning

confidence: 99%

Elevated Platelet Galectin-3 and Rho-Associated Protein Kinase Activity Are Associated with Hemodialysis Arteriovenous Shunt Dysfunction among Subjects with Diabetes Mellitus

Chen

Hsu

Chang

et al. 2019

BioMed Research International

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Introduction. Hyperglycemia is a major factor in influencing the patency rate of arteriovenous shunts, potentially associated with the RhoA/Rho-associated protein kinase (ROCK) pathway. Besides, galectin-3 mediates thrombotic mechanisms in venous thrombosis and peripheral artery disease. We hypothesized that high ROCK activity and galectin-3 levels are associated with arteriovenous shunt dysfunction. Methods. We prospectively enrolled 38 patients diagnosed with arteriovenous shunt dysfunction. 29 patients received a complete follow-up and each provided two blood samples, which were collected at the first visit for occluded status of arteriovenous shunts and 1 month later for patent status. A Western blot assay for a myosin phosphatase target subunit (MYPT) was performed to examine Rho-kinase activity. A Western blot assay for platelet galectin-3 and enzyme-linked immunosorbent assay (ELISA) for circulating galectin-3 were completed. Results. Higher platelet MYPT ratios and galectin-3 levels were identified at occluded arteriovenous shunts (MYPT ratio: 0.5 [0.3–1.4] vs. 0.4 [0.3–0.6], p = 0.01; galectin-3: 1.2 [0.4–1.6] vs. 0.7 [0.1–1.2], p = 0.0004). The plasma galectin-3 binding protein ELISA was also higher at occluded arteriovenous shunts (8.4 [6.0–9.7] μg/mL vs. 7.1 [4.5–9.1] μg/mL, p = 0.009). Biomarker ratios (occluded/patent status) trended high in patients with poorly controlled diabetes (MYPT ratio: 1.7 [1.0–3.0] vs. 1.1 [0.7–1.3], p = 0.06; galectin-3: 1.6 [1.3–3.4] vs. 1.1 [0.8–1.9], p = 0.05). Conclusion. High platelet ROCK activity and galectin-3 levels are associated with increased risk in arteriovenous shunt dysfunction, especially in patients with poorly controlled diabetes.

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Challenges in Developing New Therapies for Vascular Access Dysfunction

Cited by 8 publications

References 11 publications

Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula

Atorvastatin Reduces In Vivo Fibrin Deposition and Macrophage Accumulation, and Improves Primary Patency Duration and Maturation of Murine Arteriovenous Fistula

Use of a temporary shunt to preserve the patency of a hemodialysis graft while performing ipsilateral axillo-femoral bypass

Elevated Platelet Galectin-3 and Rho-Associated Protein Kinase Activity Are Associated with Hemodialysis Arteriovenous Shunt Dysfunction among Subjects with Diabetes Mellitus

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