Cellular and molecular mechanisms underlying hemodialysis arteriovenous fistula dysfunction and approaches to promote maturation: A vascular perspective

Abstract

Hemodialysis requires functional vascular access, which serves as the conduit for blood flow between the patient and the hemodialysis machine. The arteriovenous fistula (AVF), created by surgically connecting an artery to a nearby vein in the upper extremity, is the preferred form of vascular access for maintenance hemodialysis. Newly created AVFs must undergo a maturation process, during which the fistula vein enlarges and develops sufficient lumen size and blood flow to be used effectively for dialysis. However, since the invention of AVFs 60 years ago, rates of AVF maturation failure have remained high. Currently, no proven therapies exist to promote maturation or prevent maturation failure. This review examines the current understanding of the cellular and molecular mechanisms underlying AVF maturation failure, with particular focus on the impact of the chronic kidney disease (CKD) environment on the vascular system. In CKD, patients often have elevated levels of uremic toxins, increased oxidative stress, and chronic inflammation, all of which adversely affect the function of vascular wall cells (such as endothelial cells, vascular smooth muscle cells, and fibroblasts) and circulating cells (such as platelets and immune/inflammatory cells). The goal of this review is to explore the mechanisms influencing both native and AVF vasculature in the context of CKD. Additionally, we will discuss current therapies aimed at improving native vasculature in CKD patients, as well as investigational approaches to promote AVF maturation.

1. Introduction

The global prevalence of end-stage kidney disease (ESKD), also known as kidney failure and Stage 5 chronic kidney disease (CKD) requiring kidney replacement therapy, is estimated to be between 4.9 and 7.1 million people needing kidney replacement therapy.(1) Hemodialysis is the most common form of kidney replacement therapy in the United States (U.S.) and many developed countries.(2) Currently, more than 808,000 people in the U.S. are living with ESKD, with approximately 68% of them undergoing hemodialysis. The remaining patients either use peritoneal dialysis or have received kidney transplants.(3) Hemodialysis requires functional vascular access, which serves as the conduit for transporting blood from the patient to the dialysis machine and back. Autologous arteriovenous fistulas (AVFs), compared to other types of vascular access (i.e., synthetic arteriovenous grafts and central venous catheters), are more durable in long-term use and require less interventions, if they successfully mature (i.e., develop a sufficiently large lumen and high blood flow rate needed for dialysis).(4) For these reasons, AVFs have been the recommended form of vascular access for most patients since the Fistula First Initiative in 2003.(5) The Dialysis Outcomes and Practice Patterns Study (DOPPS) found that, in the U.S., AVF use increased from 20.7% to 26.5% between 1997 and 2003 (DOPPS I and II)(6) and to 63% and 68% in 2010 and 2013, respectively (DOPPS IV and V).(7)

In 1965, the surgeon Dr. Appel pioneered the first autologous AVF, a procedure later named the Brescia-Cimino fistula to honor the nephrologists who contributed to the concept and development of the AVF.(8) AVFs are surgically created by connecting an artery and a nearby vein directly, usually in the upper extremity. They are commonly constructed at the radiocephalic, brachiocephalic, and brachiobasilic locations (Figure 1). Approximately 49% of AVFs were located in the upper arm and 26% were in the forearm between 2009 and 2015 (DOPPS IV and V).(9) AVFs must successfully mature before they can be used for dialysis. A typical mature and functional AVF vein sees its lumen diameter growing from a preoperative value of ~2 mm to ~6 mm and the blood flow rate increasing from a preoperative value of 25 mL/min to >500 mL/ min.(10–12) AVF maturation typically requires an average time of 6-12 weeks or longer.(11) Unfortunately, a significant number of newly created AVFs do not mature. Analysis of recent data from the United States Renal Data System revealed an AVF maturation failure rate of 51%.(13)

Figure 1: Major vasculature of the arm.

The first panel shows the native vasculature commonly used for arteriovenous fistula (AVF) creation. The remaining panels show the radiocephalic, brachiocephalic, and brachiobasilic AVFs, respectively. Created in BioRender. Northrup, H. (2025) https://BioRender.com/l42a457

Historically, AVF maturation failure has been largely attributed to venous stenosis, a process involving “neointimal hyperplasia” formation (often referred to as inward remodeling) (Figure 2), which narrows the lumen, leading to reduced blood flow and increased risk of thrombosis within the fistula.(14–16) Consequently, most previous studies have focused on treatments aimed at preventing thrombosis, inflammation, and cell proliferation. In recent years, insufficient “lumen expansion” (often referred to as outward remodeling) (Figure 2) has garnered increased attention.(17, 18) Successful AVF maturation is now considered a balance between hyperplasia (inward remodeling) and lumen expansion (outward remodeling) that allows for the flow and cannulation required for dialysis. Recent research has explored treatments that modulate vasodilation and the extracellular matrix (ECM). Given the complexity of AVF maturation failure, further investigation is essential to gain a more comprehensive understanding of the underlying pathophysiology and develop effective therapies to ensure successful maturation for hemodialysis.

Figure 2: Successful and failed arteriovenous fistula (AVF) remodeling.

A) Idealized native vein. B) Idealized AVF vein showing outward remodeling. C) Idealized AVF vein showing outward remodeling with limited neointimal hyperplasia. D) Idealized AVF vein showing lack of outward remodeling. E) Idealized AVF vein showing outward remodeling with large neointimal hyperplasia. Used with permission: Northrup, H. M. (2022). Effects of Treatments on the Geometry and Vascular Biomechanics of Arteriovenous Fistulas in Rodents and Patients (Doctoral dissertation, The University of Utah).

Indeed, current therapies for AVF maturation failure focus on intervention after the dysfunction has occurred (e.g., plain balloon angioplasty, stent grafts, and drug-coated balloons). There is a lack of effective treatments to prevent maturation failure or to promote successful maturation. Thus far, landmark multicenter randomized controlled trials have reported systemic therapies to be minimally effective (Table 1). The impact of this deficit in effective clinical therapies is reflected in the Medicare costs in the U.S. Of the $2.8 billion spent on establishing vascular access for hemodialysis, most of it stemmed from AVF dysfunction or primary patency loss.(19) The financial burden of ESKD care is considered the most expensive under Medicare, with the majority of the cost attributed to dialysis treatments, which average around $100,000 per year per patient.(20) To put this in context, the average annual cost for a cardiovascular disease patient on Medicare is around $20,000.(21) Accordingly, further research focused on therapies aimed at improving AVF maturation and longevity is necessary to reduce costs and adequately address this unmet clinical need.

Table 1:

Recent and landmark clinical or pivotal studies, reported at clinicaltrials.gov, for therapies to improve arteriovenous fistula maturation.

Sponsor/National Clinical Trial Number (NCT)	Year start	Projected End	Targeted cell type	Therapy	Delivery	Mechanism of action	Phase
Focus on platelet effects
National Institute of Diabetes and Digestive and Kidney Diseases NCT03289520	2003	2007	Platelets	Clopidogrel	Oral	Antiplatelet (binds platelet P2RY12 purinergic receptor)	3
Australasian Kidney Trials Network *CTRN12607000569404	2008	2015	Many cell types	Fish oil	Oral	Pleiotropic effects (decreases platelet aggregation, blood viscosity, and inflammation; promotes vasodilation)	3
HMG-CoA reductase inhibition
National Cheng-Kung University Hospital NCT01863914	2012	2019	Many cell types	Rosuvastatin	Oral	HMG-CoA reductase inhibitor	Phase 2
Albany Medical College NCT03188978	2018	2019	Many cell types	Atorvastatin	Oral	HMG-CoA reductase inhibitor	Phase 1, Phase 2
Pancreatic elastase
Proteon Therapeutics NCT02110901	2014	2018	Smooth muscle cells	PRT-201	Perivascular	Recombinant human type 1 pancreatic elastase	Phase 3
PDE5A inhibition
University of Alabama at Birmingham NCT02414204	2017	2018	Smooth muscle cells	Sildenafil	Oral	PDE5A inhibitor	N/A
VEGF-A inhibition
Mayo Clinic NCT02695641	2019	2021	Endothelial cells	Bevacizumab	Intravenous	VEGF-A inhibition	Early Phase 1
mTOR inhibition
Vascular Therapies, Inc NCT05425056	2022	2025	Immune cells	Sirolimus eluting collagen implant (SeCl)	Perivascular	mTOR inhibition	Phase 3
Hand or arm exercise/movement
University Health Network, Toronto NCT02205944	2014	2018	Many cell types	Two types of presurgical exercise	N/A	Handgrip exercise	N/A
Changi General Hospital NCT03137680	2017	2019	Many cell types	Pre-operative forearm exercises	N/A	Softball hand exercise	N/A
Hospital General Universitario Gregorio Maranon NCT03213756	2017	2019	Many cell types	Preoperative isometric preoperative exercise	N/A	Isometric hand and arm exercises	N/A
National Taiwan University Hospital NCT03077815	2017	2018	Many cell types	Arm exercise	N/A	Gripping arm movements	N/A
Singapore General Hospital NCT03886116	2018	2021	Many cell types	Pre-operative forearm exercises	N/A	Forearm exercises	N/A
Guangdong Provincial People’s Hospital NCT03741985	2018	2019	Many cell types	Dumbbell exercise	N/A	Dumbbell exercise	N/A
Hospices Civils de Lyon NCT04034433	2019	2026	Many cell types	Perioperative handgrip training	N/A	Handgrip exercise	N/A
Taipei Medical University NCT05493046	2022	2026	Many cell types	Interactive hand exercise game	N/A	Increase handgrip strength	N/A
Physical therapy
Herlev and Gentofte Hospital NCT04011072	2019	2023	Endothelial cells, fibroblasts	Far infrared therapy	N/A	increased molecular vibration by photon absorption	N/A
Suzhou Municipal Hospital NCT06249373	2024	2026	Many cell types	Low-intensity pulse ultrasound	N/A	mechanical vibrations in tissues and cells	N/A
Stem cell therapy
Houssam Farres NCT04392206	2020	2025	Many cell types	Allogeneic adipose derived mesenchymal stem cells	Perivascular	Stem cell therapy	Phase 1
Mechanical support
VenoStent NCT05418816	2021	2024	Many cell types	Bioabsorbable perivascular wrap, SelfWrap	Perivascular	biomimetic mechanical support	N/A
VenoStent NCT06001827	2023	2027	Many cell types	Bioabsorbable perivascular wrap, SelfWrap	Perivascular	biomimetic mechanical support	N/A

^*anzctr.org au identifier

The lack of therapies for AVF maturation highlights a gap in our understanding of the underlying mechanisms. The AVF milieu is unique. Cells in AVFs are exposed to shear stress and flow conditions that are much higher and more disturbed than under normal circumstances, due to the low resistance in the arteriovenous shunt circuit. Additionally, AVFs are almost exclusively created in patients with advanced CKD (i.e., Stage 4 CKD) and ESKD (i.e., Stage 5 CKD). These patients have uremic toxins in their bloodstream, increased oxidative stress, and chronic inflammation, all of which affect cells in the vascular wall (such as endothelial cells, vascular smooth muscle cells, and fibroblasts), as well as cells in circulation (such as platelets and immune/inflammatory cells) (Figure 3).

Figure 3: Overview of the arteriovenous fistula (AVF).

Key cell types involved in AVF remodeling include vascular wall cells (such as endothelial cells, vascular smooth muscle cells, and fibroblasts) and circulating cells (such as platelets and immune/inflammatory cells). Blood flow is represented by black arrows. Neointimal hyperplasia is shown as limiting blood flow in the AVF vein. Created in BioRender. Northrup, H. (2025) https://BioRender.com/v70n709

Direct anastomosis of the low-pressure vein to the high-pressure artery allows for the redirection of arterial blood through the vein. Not only does this redirection cause an increase in venous flow rate, which is needed for the dialysis machine, but it also elevates pressure and induces flow disturbances—particularly at the arteriovenous anastomosis. AVF flow has been quantified using various parameters, including wall shear stress (WSS) and oscillatory shear index (OSI). WSS is the frictional force exerted by blood flow parallel to the vessel wall and plays a critical role in regulating endothelial cell signaling cascades. OSI is commonly used to quantify disturbed flow, with high OSI indicating oscillatory, non-unidirectional flow, and low OSI reflecting more uniform, unidirectional flow. In a prospective, multi-center clinical study (n=120), He et al. demonstrated that early WSS (1 day after AVF creation) was positively associated with greater subsequent lumen expansion, whereas OSI was negatively associated with lumen expansion.(22) This positive association between early WSS and later lumen diameter was corroborated in a larger, multi-center study (n=602).(23) Importantly, AVF location (Figure 1), postoperative venous diameter, and the presence of stenosis have also been found to influence AVF maturation.(12) These three parameters (AVF location, diameter, stenosis) altered the anastomotic geometry, thereby affecting local hemodynamics, such as WSS and OSI. While the study of hemodynamic parameters and their influence on AVF remodeling is making progress, significant gaps remain in our understanding of the underlying mechanisms. Notably, He et al.(22) reported that WSS in AVFs can reach magnitudes on the order of 1,000 dyn/cm²—far exceeding those observed in native veins (<10 dyn/cm²) and arteries (<100 dyn/cm²). These findings highlight the extreme mechanical environment of the AVF and underscore the importance of vascular mechanobiology in guiding successful AVF maturation and function.

This review aims to explore the current understanding of cell and molecular mechanisms in both native and AVF vasculature within the context of CKD. We will also discuss existing therapies aimed at improving the native vasculature in CKD patients, as well as investigational treatments designed to promote AVF maturation. The effects of abnormal blood flow on AVF maturation failure and the underlying mechanisms have been comprehensively reviewed elsewhere.(24–26)

2. Key cellular players involved in AVF remodeling

Vascular disease is a major complication of CKD and can significantly hinder the maturation of AVFs used for hemodialysis. Characterized by endothelial dysfunction, arterial stiffness, vascular calcification, chronic inflammation, and increased oxidative stress, these changes create a hostile environment for the AVF maturation process. This process involves complex interactions among various cell types, including endothelial cells (ECs), vascular smooth muscle cells (SMCs), fibroblasts, platelets, and immune/inflammatory cells (Figure 3). Crosstalk between these key cellular players promotes a pro-thrombotic, pro-inflammatory, and pro-fibrotic environment, further exacerbating vascular dysfunction and AVF maturation failure.

2.1. Endothelial cells

ECs line the inner most layer of both arteries and veins, but their functions and the hemodynamic environments they experience differ.(27) Normally, arterial ECs are adapted to high-pressure, pulsatile blood flow and play a role in regulating vascular tone and preventing thrombosis by releasing vasodilators such as nitric oxide (NO). In contrast, venous ECs are exposed to lower pressure, slower and more laminar blood flow, and lower oxygen levels.(28, 29)

In CKD, vascular endothelial damage occurs early and worsens as the disease progresses.(30) This damage is driven by systemic inflammation, oxidative stress, the accumulation of uremic toxins, and pre-existing risk factors such as hypertension, diabetes mellitus, and hyperlipidemia.(31) The main types of structural damage to the endothelium in CKD include loss of endothelial integrity, increased permeability, endothelial activation by inflammation, osteogenic changes in ECs, endothelial-to-mesenchymal transition, and EC detachment.(32) Damaged ECs in CKD exhibit impaired abilities to regulate vascular tone, inflammation, coagulation, calcification, and angiogenesis. Moreover, the number and function of progenitor endothelial cells, responsible for repairing damaged endothelium and promoting new blood vessel formation, are significantly reduced in CKD.(33)

A key mechanism underlying endothelial dysfunction in CKD is reduced NO production. L- arginine, the precursor for NO synthesis, is converted to NO by endothelial nitric oxide synthase (eNOS) in vascular ECs. Once produced, NO diffuses across cell membranes and activates guanylate cyclase in various cell types, including vascular SMCs and circulating platelets and leukocytes.(34) In vascular SMCs, guanylate cyclase activation leads to myosin light chain dephosphorylation and vasorelaxation. In platelets, NO inhibits activation, adhesion, and aggregation, while it reduces leukocyte adhesiveness. In the CKD milieu, uremic toxins such as asymmetric dimethylarginine inhibit eNOS, while excessive reactive oxygen species (ROS) react readily with NO to form peroxynitrite, a harmful compound that further reduces NO availability.

Chronic oxidative stress in CKD also leads to increased expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) on ECs, promoting the adhesion and infiltration of immune cells such monocytes and lymphocytes. This creates a vicious cycle of endothelial damage, with ECs becoming more activated and releasing more pro-thrombotic and pro-inflammatory factors.(35) Furthermore, ECs in CKD can undergo a phenotypic switch toward a more osteogenic (bone-like) state. This shift leads to the secretion of endothelial microparticles containing adhesion molecules, microRNAs, and osteogenic factors (such as osteocalcin and bone morphogenetic proteins), which can stimulate both ECs and vascular SMCs, contributing to vascular calcification.(36) Damaged ECs also express more pro-thrombotic factors, including tissue factor and von Willebrand factor, while producing less tissue plasminogen activator, promoting a pro-thrombotic state and fibrosis.(37)

In the AVF context, animal studies show that eNOS overexpression in mice improve AVF remodeling (i.e., limited neointimal hyperplasia and improved blood flow in AVFs), whereas eNOS knockout worsens AVF remodeling.(38–41) Jumonji domain-containing protein-3 (JMJD3), a histone H3 lysine 27 demethylase, promotes endothelial regeneration. It has been found that endothelial JMJD3 expression was negatively associated with neointimal hyperplasia of AVFs in patients, and knockout of endothelial JMJD3 decreased eNOS expression/NO production and increased neointimal hyperplasia formation in a mouse AVF model.(42) Bulk RNA sequencing of human AVF samples, obtained from patients undergoing 2-stage AVF creation surgery, revealed 17 endothelium- predominant genes that were downregulated in AVFs that failed compared to AVFs that matured.(43) Notable downregulated genes were eNOS, ICAM2, SELL, APOLD1, ARG2, SELP, PALMD, and SRGN.(43) The authors speculated that this downregulation was related to a lower level of endothelial specific transcription factors or due to vastatin, a collagen VIII–derived matrikine, from the upregulation in collagen VIII which was also prominent in human AVFs that failed to mature.(43)

2.2. Vascular smooth muscle cells

Vascular SMCs are the main constitutive stromal cells found in the medial layer of blood vessels where they regulate vascular tone and maintain structural integrity.(44, 45) In arteries, SMCs are more contractile, responding to vasoactive signals to regulate blood pressure. Conversely, veins contain fewer SMCs and are more compliant, designed to accommodate larger blood volumes at lower pressures.

In CKD, vascular SMCs undergo several changes, including phenotypic modulation, increased proliferation, and migration, which collectively lead to pathological vascular remodeling and medial calcification.(36) Medial calcification, along with intimal calcification (also known as atherosclerotic calcification and thought to originate from atherosclerosis), is prominent and is generally considered an irreversible process in CKD.(36) These pathological changes are driven by factors such as hypercalcemia, hyperphosphatemia, hyperthyroidism, oxidative stress, inflammation, alpha-Klotho deficiency, and uremia.(36)

The pathogenesis of vascular SMC changes in CKD have been extensively reviewed, and the phenotypic switching of vascular SMCs is central to theses pathological outcomes.(36, 46–48) In their healthy state, vascular SMCs maintain a contractile phenotype, characterized by the expression of smooth muscle alpha-actin and myosin heavy chain.(49) However, in patients with CKD, vascular SMCs shift to a synthetic phenotype, marked by increased expression of ECM proteins such as collagen, elastin, vimentin, and matrix metalloproteinases, as well as pro-inflammatory cytokines and osteogenic genes.(46, 49–52) This transition leads to the development of various vascular SMC subtypes, including myofibroblast, macrophage-like, osteogenic, and senescent vascular SMCs, all of which contribute to arterial fibrosis, stiffness, and calcification.

In the AVF context, a recent animal study identified a long non-coding RNA, LncDACH1, as a regulator of neointimal hyperplasia in the AVF.(53) Using smooth muscle-specific knockout and overexpression mouse models, the researchers found that KLF9 downregulates LncDACH1; in turn, LncDACH1 promotes the development of neointimal hyperplasia via the AKT/SRPK1/HSP90 signaling pathway.(53) Another group explored the role of the mineralocorticoid receptor (MR) in AVF remodeling in human and mouse AVFs.(54) Dysfunctional fistulas, collected from patients undergoing surgical revision, had increased MR expression and decreased smooth muscle myosin heavy chain, along with elevated osteopontin and cellular proliferation.(54) In rat AVF models, pharmacologic targeting of MR with finerenone significantly improved AVF outcomes, characterized by increased lumen diameters and flow volume, reduced medial fibrosis, and inhibited SMC phenotypic shifting from contractile to synthetic. These beneficial effects of finerenone were attributed to reduced activity of the EGFR-ERK1/2 signaling pathway.(54)

Using a vascular SMC lineage tracing reporter mouse model, researchers have tracked vascular SMC fate in a rat AVF model.(55) They induced the medial layer SMCs with tamoxifen to express green fluorescent protein (GFP) prior to AVF surgery. Four weeks after AVF creation, they observed medial layer thickening in the vein, composed primarily of differentiated GFP+/MYH11+/Ki67+ SMCs. In contrast, the neointimal hyperplasia at the anastomosis was made up of dedifferentiated GFP+/MYH11− VSMCs. These findings suggest that vascular SMC phenotype switching differs between medial wall thickening and neointimal hyperplasia.(55) The anatomical sources of neointimal cells in AVFs have been comprehensively reviewed elsewhere.(56)

2.3. Fibroblasts

Fibroblasts are specialized cells essential for the formation of connective tissue, which provides structural support to various organs and tissues throughout the body. These cells secrete collagen, a key protein that helps maintain the strength and integrity of tissues.(57) In blood vessels, fibroblasts are predominantly located in the adventitia, the outermost layer of the blood vessel, where they are typically in a quiescent state and lack contractile stress fibers (microfilaments)(58). Although few studies have explored their embryonic origins, these fibroblasts are thought to arise from local mesenchymal cell populations.(58) Vascular fibroblasts are challenging to define in vivo due to the variability in gene expression, even in their resting state. Like interstitial fibroblasts, activated adventitial fibroblasts proliferate, deposit ECM proteins, and secrete pro-inflammatory cytokines and chemokines.(58) These activated fibroblasts—often referred to as myofibroblasts—express contractile proteins like smooth muscle alpha-actin, which is also found in vascular SMCs as mentioned above.(57)

Dysfunctional vascular fibroblasts play a critical role in the progression of arterial diseases, including atherosclerosis, hypertension, and aortic dissection.(59) In the vein, these fibroblasts can be activated in response to changes in wall tension and acquire a contractile apparatus, including microfilaments, fibronexus junctions, and other features commonly found in vascular SMCs.(56) CKD significantly affects vascular fibroblasts, primarily by causing an increase in the level of fibroblast growth factor 23 (FGF-23) which is associated with vascular calcification in CKD patients.(60)

In the context of AVF, the ECM modifications induced by myofibroblasts play a crucial role in maintaining hemostasis during the final stages of AVF remodeling when the lumen size and wall thickness have grown adequately, allowing adaptation to arterial flow.(61) Evidence from in vitro cultures and animal models of restenosis suggests that adventitial myofibroblasts have a remarkable ability to migrate toward the intima in response to injury, contributing to the formation of neointimal hyperplasia.(56) However, vascular SMCs can also dedifferentiate into myofibroblasts. It remains unclear whether the different origins of these myofibroblasts (from SMCs or fibroblasts or else) results in identical or distinct phenotypes and contributions to the AVF maturation process. Additional AVF studies have looked into FGF21, which is a secreted protein associated with various disease states including oxidative stress, inflammation, and atherosclerosis.(62) The serum levels of FGF21 were associated with AVF functional patency loss in patients.(63) In animal studies, parathyroid hormone was found to increase vascular wall thickness and myofibroblasts in a mouse AVF model, and parathyroid hormone increased integrin beta-6. The authors speculated that it may indicate a transition of fibroblasts to myofibroblasts.(64) Given the established role of parathyroid hormone in regulating FGF-23,(65) it is possible that parathyroid hormone led to increased FGF-23 levels, which—as previously discussed in the context of CKD—is associated with vascular calcification. However, the authors did not investigate FGF-23 or vascular calcification in relation to parathyroid hormone treatment.(64)

2.4. Platelets

Platelets are small, anucleate cells that circulate in the blood in large quantities and play a vital role in hemostasis.(66) In addition to their role in clot formation, platelets also contribute to immune and inflammatory responses. These platelets remain inactive under a healthy state but become activated upon injury (i.e., vascular damage). Upon injury, platelets adhere to the subendothelial surface through the interactions between the platelet receptor GPIb-IX and von Willebrand factor, forming a plug, which is further stabilized by fibrin strands through the coagulation cascade. Activated platelets release various chemokines and cytokines, including CXCL4, CXCL5, CXCL8, CCL5, IL-1β, TGFβ and tumor necrosis factor-alpha, as well as signaling molecules like P-selectin, damage-associated molecular patterns, and growth factors (vascular endothelial growth factor (VEGF) and platelet-derived growth factor). These molecules promote leukocyte recruitment, differentiation, and phagocytosis, aiding tissue repair and protecting from pathogens.(66)

In patients with CKD, changes in platelet number and function have been inconsistently reported. Most patients with CKD who are not receiving dialysis do not exhibit a significant reduction in platelet number, while those on maintenance hemodialysis often experience a 20% decrease.(67) The cause of this reduction is unclear but may be due to increased consumption related to the extracorporeal circuit or dialysis membrane-induced platelet aggregation, or potentially insufficient platelet production by megakaryocytes. In addition to reduced platelet numbers, patients with CKD exhibit platelet dysfunction with impaired adhesion, aggregation, granule secretion, thromboxane A2 generation, and platelet-mediated clot retraction.(68–70) These abnormalities can result in either thrombotic or hemorrhagic complications.(68–70) CKD is also associated with endothelial injury as described above. These changes reduce antiplatelet mediators, promoting platelet activation and aggregation. Consequently, patients with CKD, particularly before starting dialysis, may have a higher thrombotic tendency, with platelet hyperactivity exacerbating inflammatory and immune responses.(68, 71)

During AVF creation, the blood vessel wall is injured, leading to platelet recruitment. Platelet factor 4, a protein expressed in platelets, plays a crucial role in promoting coagulation. Platelet factor 4 is also implicated in fibrosis and has been shown to be upregulated in AVFs, particularly those that fail to mature.(72) While stenosis and thrombosis are the primary causes of AVF maturation failure in clinical practice, there is limited mechanistic research on platelets. Clinical trials have investigated the use of antithrombotic drugs, such as dipyridamole and clopidogrel, to prevent thrombosis and improve AVF outcomes. Although both drugs were effective in reducing thrombosis, they did not significantly enhance AVF maturation.(73, 74) Similarly, neither aspirin or fish oil treatment, which has platelet aggregation inhibitory properties, had significant effects on AVF usability.(75) This limited impact from clinical trials may explain the relative paucity of studies on platelet mechanisms in AVF dysfunction.

2.5. Immune/inflammatory cells

Inflammatory cells circulating in the bloodstream primarily include neutrophils, monocytes, lymphocytes (T cells, B cells, and natural killer cells), eosinophils, and basophils. In patients with CKD, there are often increases in circulating neutrophils, monocytes, and pro-inflammatory lymphocytes, while regulatory T cells, particularly central memory CD4+ and CD8+ T cells, are significantly depleted in patients with ESKD.(76–79). Additionally, the proportion of B cells decreases.(77)

As mentioned above, ECs in CKD express elevated levels of adhesion molecules such as VCAM-1, ICAM-1, and E-selectin, which promote the recruitment and adhesion of inflammatory cells, including neutrophils, monocytes, and lymphocytes.(35, 80) These adhered cells secrete pro- inflammatory cytokines and ROS, exacerbating endothelial dysfunction and amplifying vascular inflammation. In CKD, monocytes and macrophages are highly activated, producing elevated pro- inflammatory cytokines such as IL-1β, TNF-α, and monocyte chemoattractant protein-1. They also express angiotensin converting enzyme and secrete TGFβ, which stimulate vascular cells to produce excessive amounts of ECM, leading to vascular fibrosis and stenosis.(79, 81, 82) Additionally, activated monocytes and macrophages release cytokines and growth factors that induce vascular SMC de-differentiation or activation, driving abnormal vessel remodeling such as neointimal hyperplasia.(79) Platelet activation often parallels this process, promoting thrombotic occlusion and further exacerbating vascular damage in CKD.(83) Many studies on AVF remodeling have reported increased inflammatory markers in both human AVF samples and animal models of AVFs; consequently, several excellent reviews focusing on immune and inflammatory cells are available.(84, 85)

3. Vascular function and AVF remodeling

3.1. Association between preoperative vascular function and postoperative venous remodeling in AVFs in patients

Vasodilation and outward remodeling of both the artery and vein are essential for the successful maturation of a newly created AVF (Figure 2).(86) Endothelial dysfunction (characterized by a shift toward proinflammatory, prothrombotic, and reduced vasodilatory states)(87) and increased vascular stiffness (defined as a reduction in the flexibility of the vascular wall to expansion when blood volume increases) are commonly observed in patients with ESKD.(30, 71) The Hemodialysis Fistula Maturation (HFM) Study was a prospective, multicenter cohort study on AVF maturation, funded by the National Institute of Diabetes and Digestive and Kidney Diseases. It was designed to identify clinical and biological factors associated with fistula maturation outcomes.(88) The HFM Study proposed that pre-existing impairments in endothelial function, vascular SMC function, arterial compliance, and venous distensibility disrupt normal arterial and venous dilation processes and impede the vascular remodeling required for successful fistula maturation.(89) While a couple of earlier studies explored the association between arterial elasticity and fistula outcomes,(90, 91) and one study examined the link between venous capacitance and fistula maturation,(92) these studies were limited by small sample sizes (<100 patients), restricting their ability to account for vascular variability, adjust for clinical confounders, and generalize findings (23,24). In contrast, the HFM Study incorporated a wide range of measurements that assessed various vessel types and sizes, as well as both endothelium-dependent and endothelium-independent vasodilation.(89)

The HFM Study participants (n = 602, 7 centers) underwent standardized preoperative ultrasounds of the upper-extremity arteries and veins, along with five vascular function tests within 45 days before AVF surgical creation: (i) endothelium-dependent vasodilation via brachial artery flow- mediated dilation (FMD), (ii) endothelium-independent vasodilation via brachial artery nitroglycerin- mediated dilation (NMD), which assesses the capacity of arterial SMCs to respond to the NO donor nitroglycerin, (iii) stiffness of the elastic aorta via carotid-femoral pulse wave velocity, (iv) stiffness of the muscular arteries in the upper extremity via carotid-radial pulse wave velocity, and (v) venous capacitance in the upper extremity via venous occlusion plethysmography. Participants then underwent standardized postoperative AVF ultrasounds at 1 day, 2 weeks, and 6 weeks to measure AVF vein flow rate and lumen diameter. The relationship of each of the preoperative vascular functional parameters with subsequent AVF characteristics was examined by using mixed-effects multiple regression analyses.(89) After controlling for AVF location, preoperative ultrasound measurements (preoperative inflow artery diameter, minimum vein diameter, and brachial artery flow), and demographic factors (age, sex, race, and dialysis status), greater brachial artery FMD was correlated with enhanced 6-week AVF blood flow and diameter (for every 10% difference in FMD: change in blood flow rate = 11.6%, 95% CI, 0.6% to 23.9%, P=0.04; change in diameter = 0.31 mm, 95% CI, 0.05 to 0.57 mm, P=0.02). Similarly, higher brachial artery NMD was also associated with increased 6-week AVF blood flow and diameter (for every 10% difference in NMD: change in blood flow rate = 14.0%, 95% CI, 3.7% to 25.3%, P<0.01; change in diameter = 0.45 mm, 95% CI, 0.25 to 0.65 mm, P<0.001). In contrast, no significant or consistent relationships were found between other preoperative vascular functional parameters and postoperative AVF characteristics. Specifically, although carotid-femoral pulse wave velocity exhibited a trend toward an inverse relationship with 6- week AVF diameter, neither carotid-femoral nor carotid-radial pulse wave velocity showed statistically significant relationships with AVF blood flow. Although there was a weak positive relationship between venous capacitance and AVF diameter at 2 weeks, there was no consistent relationship of venous capacitance with AVF blood flow or diameter across the three consecutive postoperative assessments.

It is important to recognize that the inability to detect associations between AVF outcomes and pre-operative vascular functional parameters assessed by pulse wave velocity and venous occlusion plethysmography may reflect the inherent limitations and relative insensitivity of these tests. Pulse wave velocity techniques are indirect measures of arterial stiffness, influenced by the combined stiffness of multiple arteries, which may vary in their individual stiffness profiles. Similarly, venous occlusion plethysmography has limited reliability in assessing the compliance of large veins. Consequently, more advanced and precise technologies are needed to accurately measure the stiffness of the arteries and veins used for AVF creation. Additionally, it is important to note that a small preoperative arterial diameter (e.g., 3 mm) can result in high AVF flow volumes. This is often observed in high-flow AVFs that require banding to reduce excessive flow rate. A flow rate greater than 1500 mL/min can lead to complications such as cardiac overload, post-dialysis bleeding, and elevated venous pressure. While techniques vary, banding is typically performed near the arterial juxta-anastomosis to reduce the arterial diameter to between 2.5 and 6 mm, thereby lowering flow rate to a normal (600–1500 mL/min) or low (<600 mL/min) range, while preserving AVF patency and usability for hemodialysis.(93) Therefore, when evaluating vessels for AVF creation, the smallest preoperative inflow arterial diameter should be taken into consideration.

Nonetheless, the observed association of preoperative brachial artery FMD and NMD with favorable changes in the AVF vein after creation highlights the critical role of vasodilatory response integrity in promoting AVF maturation, at least by the 6-week postoperative mark.(94) Therefore, a better understanding of impaired conduit artery dilation in ESKD patients may be key to uncovering the underlying causes of AVF maturation failure and developing effective treatments to promote AVF maturation.

3.2. Clinical evidence for impaired conduit artery endothelium-dependent dilation in CKD and ESKD

Brachial artery FMD and NMD are commonly used, non-invasive assessments of macrovascular endothelial and smooth muscle cell functions, respectively.(95) These tests are typically expressed as the percentage changes in brachial artery diameter after ischemia (FMD) and after nitroglycerin administration (NMD). Both have been extensively used to investigate vascular function in patients with CKD and ESKD, establishing clear evidence of endothelial dysfunction in CKD and ESKD patients, while vascular smooth muscle dilation in response to NO appears preserved.

Yilmaz et al. (96) documented a progressive decline in endothelial function as CKD progresses from Stage 1 to Stage 5, despite preserved endothelium-independent vasodilatory response as shown by NMD, which suggests that arterial smooth muscle dilation in response to NO remains intact. Katulka et al. (97) also found a moderate association between endothelial function and estimated glomerular filtration rate in patients with Stage 3-5 CKD, though endothelium-independent vasodilation was not assessed in their study.

Conduit artery endothelial dysfunction, as assessed by brachial artery FMD, is also present in patients with ESKD who are on maintenance hemodialysis compared to healthy controls.(98–101) Joannides et al. (102) reported similar findings using radial artery FMD testing in ESKD patients compared to healthy controls. Importantly, endothelium-independent vasodilation remains intact in patients with dialysis-dependent ESKD.(98, 102, 103) The HFM Study did not include healthy, non- CKD controls; however, it reported that FMD was higher among patients undergoing maintenance dialysis than in those not yet on dialysis.(104) This finding, where FMD was greater in dialysis patients compared to pre-dialysis patients, is consistent with the dialytic removal of mediators of endothelial dysfunction. Importantly, it suggests that endothelial function may be modifiable in the ESKD population.

3.3. Approach to improve conduit artery dilation in CKD and ESKD

Several pharmacological agents commonly prescribed to manage CKD-related comorbidities have demonstrated direct and/or indirect protective effects on endothelial function.(105) However, their safety in ESKD patients require further investigation in future studies. Several of these studies have explored whether these pharmacological agents can improve conduit artery endothelial function in patients with CKD Stages 1-5.(106–109) Approaches for improving AVFs are discussed in Section 4.

3.3.1. Statins.

Statins, commonly prescribed for managing proteinuria-related hyperlipidemia in CKD patients, are known for their lipid-lowering and anti-inflammatory effects.(105, 110) For instance, atorvastatin has been shown to improve lipid profiles and enhance conduit artery endothelial function in CKD patients, partly by increasing eNOS activity and NO production.(111, 112)

3.3.2. Anti-inflammatory and antioxidant therapies.

Several drugs targeting inflammation and ROS have been studied in CKD patients. For example, treatment with rilonacept, an IL-1 blocker, improves conduit artery endothelial function and reduces high-sensitivity C-reactive protein concentrations and endothelial cell expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in patients with Stage 3-4 CKD, suggesting both anti-inflammatory and antioxidant benefits.(113) Allopurinol, a xanthine oxidase inhibitor used to manage hyperuricemia, has yielded mixed results regarding its effects on endothelial function. Some studies report no significant changes,(114, 115) while others have shown improvements in conduit artery endothelial function.(116, 117) These discrepancies for allopurinol may be due to variations in treatment duration, disease severity, and patient populations, and have been observed for vitamin C. For example, Ghiadoni et al. (109) documented that oral vitamin C administration (2 g) to patients with non-dialysis- dependent Stage 3-5 CKD and hemodialysis-dependent ESKD reduced oxidative stress biomarkers and enhanced antioxidant biomarkers in their plasma. However, these favorable changes were accompanied by an improvement in conduit artery endothelial function only in patients with hemodialysis-dependent ESKD, without affecting endothelium-independent vasodilation. In contrast, Cross et al. (118) found no improvement in conduit artery endothelial function, assessed in both the brachial and radial arteries, after parenteral administration of vitamin C in patients with non-dialysis- dependent Stage 4-5 CKD or hemodialysis-dependent ESKD, despite increases in serum antioxidant activity. The lack of improvement may, in part, be explained by differences in the method and dosage of vitamin C administration. In their study, vitamin C was administered intra-arterially (25 mg/min) for patients with non-dialysis-dependent Stage 4-5 CKD and intravenously (3 g) for patients with hemodialysis-dependent ESKD.(118)

3.3.3. Anti-hypertensive medications.

Anti-hypertensive agents are also commonly prescribed to manage hypertension, a prevalent comorbidity in CKD.(105) In CKD patients with type 2 diabetes mellitus (T2DM), angiotensin converting enzyme inhibition with ramipril improved conduit artery endothelial function,(119) suggesting that renin-angiotensin system activation plays a crucial role in endothelial function in CKD patients with T2DM. Similar improvements in endothelial function have also been observed in non-dialysis-dependent CKD patients treated with either ramipril or valsartan (an angiotensin II receptor blocker).(120) Spironolactone, which inhibits aldosterone by binding to mineralocorticoid receptors, has been shown to improve forearm microvascular endothelial function in ESKD patients on hemodialysis,(121) though a role of microvascular endothelial function in AVF remodeling has not yet been investigated.

3.3.4. Sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Given the high prevalence of T2DM in CKD patients,(105) treatment with pharmacologic agents such as SGLT2 inhibitors may offer an attractive therapeutic option. Recent studies have shown that SGLT2 inhibitors like empagliflozin (122) and dapagliflozin (123) improve conduit artery endothelial function in T2DM patients, suggesting that these drugs may have vasoprotective effects that extend to CKD and/or ESKD patients.

4. Investigational treatments to improve AVF remodeling

While many potential treatments for AVF maturation have been explored, none have yet achieved definitive success in clinical trials (Table 1). However, ongoing research continues to offer promising avenues for future breakthroughs. AVF maturation involves complex vascular remodeling, and several investigational treatments are targeting the underlying mechanisms that hinder fistula development, with the goal of enhancing this process.

4.1. Pharmacological agents

4.1.1. Promote vasodilation.

Nitric oxide is essential for vasodilation, and therapies aimed at increasing its bioavailability could help promote AVF maturation. NO-releasing gels applied to the AVF anastomosis (Figure 4) have been shown to promote outward remodeling and inhibit neointimal hyperplasia in a rat AVF model.(38) A trial sponsored by Duke University aimed to enhance NO bioavailability in patients using forearm exercises or nitroglycerin ointment; however, the study was terminated due to recruitment challenges (ClinicalTrials.gov ID: NCT02164318). Sildenafil, a phosphodiesterase type 5A (PDE5A) inhibitor, facilitates smooth muscle relaxation and vessel dilation through the cyclic guanosine monophosphate pathway. In a rat AVF model, sildenafil was added to drinking water, improving hemodynamics and promoting AVF vein remodeling.(124) A small clinical trial in 2019 suggested that sildenafil treatment improved FMD in AVF patients, although the trial was limited by a small sample size and did not progress to phase trial status (ClinicalTrials.gov ID: NCT02414204).

Figure 4: Local drug delivery mechanisms.

Localized wrap (left panel) and gel (right panel) are placed around or at the perivascular anastomosis of the arteriovenous fistula during creation surgery. Created in BioRender. Northrup, H. (2025) https://BioRender.com/p91d282

4.1.2. Anti-thrombosis.

Clopidogrel, a thienopyridine derivative, binds specifically and irreversibly to the platelet P2RY12 purinergic receptor, inhibiting adenosine diphosphate-mediated platelet activation and aggregation. Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the Dialysis Access Consortium clopidogrel study was a multicenter, randomized, double-blind, placebo-controlled trial conducted from 2003 to 2007 to examine the effects of clopidogrel on AVF thrombosis and suitability for dialysis.(125) Clopidogrel reduces the frequency of early thrombosis in newly created AVFs but does not increase the proportion of fistulas that mature and become suitable for dialysis.(73) Vorapaxar, a platelet thrombin receptor inhibitor, was studied for its potential therapeutic effects in a clinical trial conducted from 2015 to 2017. While only a few AVFs matured successfully, the results suggested that vorapaxar’s efficacy in promoting AVF maturation may be limited (ClinicalTrials.gov ID: NCT02475837).(126) Omega-3 fatty acids such as in fish oils are known to reduce thrombosis through the inhibition of platelet aggregation. Additionally, it has been shown to decrease blood viscosity, promoted vasodilation, inhibit smooth muscle cell proliferation, improve red blood cell flexibility, and has anti-inflammatory effects. The Omega-3 Fatty Acids and Aspirin in Vascular Access Outcomes in Renal Disease, or FAVOURED trial, investigated not only fish oil but aspirin as well on their effects on AVF failure. Like many of the previously mentioned studies, they found that neither fish oil nor aspirin reduced AVF maturation failure within 12 months after AVF creation (127)(anzctr.org au identifier: CTRN12607000569404).

4.1.3. Anti-proliferation, anti-inflammation, and anti-oxidative stress.

Neointimal hyperplasia in AVF causes stenosis and results from excessive cell proliferation, which may be driven by inflammation and/or oxidative stress. Matsubara et al. demonstrated the role of inflammation in AVF by inhibiting T-cells by Cyclosporine in mice, finding that T-cells regulate the accumulation of macrophages in the AVF venous wall.(128) Paclitaxel, an anti-proliferative drug used in drug-coated balloons, has been successful in preventing restenosis but has not yet proven effective in improving AVF maturation.(129–132) Similarly, known for use in drug-coated balloon angioplasty, sirolimus has not shown significant success for AVF maturation. However, a sirolimus-eluting collagen implant is currently undergoing clinical testing (ClinicalTrials.gov ID: NCT05425056).(133) This implant is placed around the anastomosis of the AVF during its creation surgery (Figure 4). Prednisolone, a corticosteroid that reduces inflammation, has been tested but has not demonstrated lasting success.(134) Despite the lack of successful pharmacological treatments targeting proliferation and inflammation, several novel therapies continue to show potential for improving AVF maturation. For example, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow in rat AVFs.(135) Further, the silencing of molecules such as VEGF-A, ADAM metallopeptidase with thrombospondin type 1 motif 1, and microRNA-21—which promote cell proliferation—using lentiviral vectors, has been shown to reduce venous stenosis in mouse AVFs.(136–138) A Phase 1 clinical trial using the VEGF-A monoclonal antibody bevacizumab was initiated in 2019 but was withdrawn due to enrollment issues (ClinicalTrials.gov ID: NCT02695641).

4.1.4. ECM modification.

AVF stenosis can result from the loss of compliance in fibrotic areas of the fistula, which converts neointimal hyperplasia into an occlusive feature.(139) Vonapanitase, which degrades elastin, is applied to the external surface of the blood vessel during AVF surgery to break down elastin fibers within the vessel wall. This degradation process is thought to promote outward remodeling, but testing of this therapeutic approach in Phase II and III clinical trials has not shown any benefit.(140) Delivery of beta-aminopropionitrile, a fibrosis inhibitor that blocks lysyl oxidase, by vascular wraps (Figure 4) increased AVF blood flow in a rat AVF model.(141) However, local application of a natural vascular scaffolding compound (4-amino-1,8-naphthalamide), which interlinks collagen and elastin via photoactivation to preserve vascular integrity, at the anastomosis during creation surgery increased AVF lumen diameter in a rat AVF model.(142) These findings from animal models suggest that ECM dynamics and/or turnover play an important role in the AVF maturation process.

4.1.5. Statin.

A previous retrospective study suggested that atorvastatin improved AVF primary patency compared to other statins or no statin use.(143) Additionally, use of atorvastatin was associated with favorable outward remodeling, preserved blood flow, and longer duration of primary AVF patency in a mouse model.(144) In a clinical trial aimed at assessing its effect on AVF maturation, patients were to receive atorvastatin daily for 2 weeks before AVF creation and for 6 weeks following creation, with the primary endpoints being AVF diameter and blood flow 6 weeks after creation. However, the trial was withdrawn due to recruitment issues (ClinicalTrials.gov ID: NCT03188978). In a clinical trial in Taiwan, 60 patients with T2DM undergoing AVF creation surgery were given either rosuvastatin or a placebo daily, starting 1 week before surgery and continuing for 3 weeks after. However, rosuvastatin therapy did not show any significant benefits compared to the placebo group (ClinicalTrials.gov ID: NCT01863914).(145) A retrospective, longitudinal cohort study found that statin did not have a beneficial effect on AVF patency.(74)

4.1.6. Senolytics.

Senescence has been reported in mouse and rat AVFs.(146, 147) Senescence markers (p16, p21, SA-β-gal) and senescence-associated secretory phenotype features occurred in both arterial and venous limbs shortly after anastomosis; over time, senescence diminished as the fistula remodeled. The senolytic fisetin increased AVF blood flow and lumen area over 3 weeks, suggesting therapeutic potential.(146)

4.2. Non-pharmacological therapies

4.2.1. Low-intensity pulsed ultrasound (LIPUS).

In this trial conducted in China, patients wear a portable LIPUS device at the anastomotic site of the AVF for 20 minutes, three times a week, for 12 weeks. The study started in February 2024 and is currently recruiting patients (ClinicalTrials.gov ID: NCT06249373). To the best of our knowledge, there are currently no published papers on LIPUS therapy for AVF. However, there have been studies showing the benefits of LIPUS on myocardial ischemia in a porcine model (148) and peripheral arterial disease in patients with Buerger disease.(149) The rationale for using LIPUS in AVF may stem from studies showing that ultrasound can induce NO release via increasing shear stress.(149) However, LIPUS has also been shown to increase endothelial cell extracellular matrix section and angiogenesis,(149) which are sometimes viewed as a hinderance to AVF maturation.(150)

4.2.2. Far infrared therapy (FIT).

In a recent clinical trial, patients received 40 minutes of infrared radiation at the site of their AVF during dialysis for one year. This trial has just been completed, and the results have not yet been released. Lindhard et al. recently reported that after one treatment with FIT during dialysis, there was a significant reduction in soluble VCAM-1 and soluble ICAM-1 levels. However, the authors concluded that their findings did not support the hypothesis that FIT during dialysis provides a vasoprotective effect after a single treatment (ClinicalTrials.gov ID: NCT04011072).(151)

4.2.3. Exercise interventions.

There has been a significant amount of research on exercise as a therapeutic approach. The most common exercise studied is handgrip exercise. A quick search on ClinicalTrials.gov reveals at least seven different handgrip trials for AVF maturation therapy, starting as early as 2008 (ClinicalTrials.gov ID: NCT05493046, NCT04034433, NCT03886116, NCT03741985, NCT03137680, NCT02205944, NCT01061008). These trials have taken place, or are ongoing, in the United Kingdom, Canada, Singapore, China, France, and Taiwan. Most of these studies involved using a ball that patients would grip for a specified duration, generally 20-60 minutes per day, over a set number of weeks, either preoperatively, postoperatively, or both. Some studies, however, used different types of exercises and compared them to ball exercises as a control. In 2022, Nantakool et al. published a review article on upper limb exercise as a therapy for AVF maturation, which included data from nine studies. They found that there was insufficient data to analyze the effects of preoperative exercise on AVF maturation. Regarding postoperative exercise, they concluded that study parameters made the effect of exercise on AVF maturation unclear.(152) The 2019 Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines state: “There is inadequate evidence for KDOQI to make a recommendation on the use of upper extremity exercise to facilitate postoperative AVF maturation”.(153)

4.2.4. Mechanical support devices.

Alternative therapies under investigation include those offering mechanical support for the AVF. A pivotal trial sponsored by Venostent in the U.S. is currently ongoing to assess the safety and efficacy of a bioabsorbable perivascular wrap called SelfWrap. The wrap is applied around the perivascular area of the AVF (Figure 4) during surgery to provide mechanical support. This study is currently enrolling patients (ClinicalTrials.gov ID: NCT06001827). VasQ is a device that also provides mechanical support. It is a nitinol-based device implanted around the artery and vein during the surgical creation of an AVF. Numerous studies on VasQ have led to its FDA clearance for use in AVF. The data show that fistulas with VasQ led to a high percentage of being used for dialysis.(154–157)

4.2.5. Biological therapies.

A Phase 1 clinical study is currently recruiting patients to evaluate the safety of allogeneic adipose-derived mesenchymal stem cell therapy. Mesenchymal stem cells, derived from the patient’s adipose tissue, are isolated and cultured. During AVF creation surgery, the stem cells are administered in Lactated Ringer’s solution to the perivasculature of the distal artery near the anastomosis (ClinicalTrials.gov ID: NCT04392206).(158) The rationale for this study is that MSCs can limit the inflammatory process and consequently reduce neointimal hyperplasia formation. A preclinical study in mice showed that administration of human adipose-derived MSCs improved AVF patency by reducing neointimal hyperplasia development as hypothesized.(158)

5. Conclusions

The AVF environment is unique and complicated. The vascular system and its key cell players in both arteries and veins (such as ECs, vascular SMCs, fibroblasts, platelets, and immune/inflammatory cells) are significantly compromised in CKD, creating substantial challenges for successful AVF maturation. Vascular dysfunction, in particular endothelial dysfunction, has been shown to play a central role in the maturation process. While no therapies have yet been proven to definitively and effectively prevent AVF maturation failure or promote successful maturation, several promising approaches are currently under investigation. Recent clinical trials have shifted focus from earlier strategies that targeted inhibiting thrombosis and neointimal hyperplasia, to now prioritizing the improvement of vascular function and ECM. Ongoing research continues to provide valuable insights, offering hope that these evolving strategies may ultimately lead to successful therapies for AVF maturation, a significant unmet clinical need.