Muscle Wasting and Arteriovenous Fistula Nonmaturation in Kidney Failure

In the United States, nearly 70% of kidney failure patients use hemodialysis as the KRT, which requires a vascular access to transport blood between the patient and the dialysis machine. Arteriovenous (AV) fistulas, created by surgically connecting a vein to a nearby artery in the arm, are the preferred vascular access for long-term hemodialysis. A typical functional AV fistula vein has its lumen diameter growing from a preoperative value of approximately 2 to 6 mm and blood flow rate increasing from 25 to >500 ml/min, in a process known as AV fistula maturation. This puts the vein in a tremendous stress, and approximately 40%–60% of newly created fistulas do not mature.¹ AV fistula maturation failure is commonly identified through angiographic stenosis at or near the anastomosis. Through histologic analysis, a retrospective single-center study of 161 patients revealed that AV fistula maturation failure was more likely when both high postoperative medial fibrosis and neointimal hyperplasia were present.² The fibrotic AV fistula vein wall loses its compliance due to excessive extracellular matrix deposition, and the hyperplastic intima becomes obstructive and stenotic, making it less expandable. Despite the high prevalence of AV fistula maturation failure, the underlying mechanisms remain poorly understood, hindering clinical trial success.

In this issue of JASN, Wu et al.³ investigate a provocative hypothesis that muscle wasting, a common feature of advanced CKD, might play a role in AV fistula maturation failure. Atrophied skeletal muscle secretes myostatin, which promotes muscle catabolism, muscle fibrosis, inflammation, and atherosclerosis.⁴ In this study, AV fistulas in both healthy mice treated with myostatin and mice with nephrectomy-induced CKD exhibited increased adventitial fibrosis and neointimal hyperplasia formation compared with healthy controls. Furthermore, blocking myostatin function with an antimyostatin peptibody (ATA842) reduced adventitial fibrosis and neointima in AV fistulas of CKD mice, while also improving their body weight and muscle size. In mechanistic studies using cultured adventitial mesenchymal stem cells (i.e., PDGF receptor A positive cells isolated from the adventitial layer of murine thoracic aorta), the investigators discovered that myostatin induced yes-associated protein 1 (YAP1) expression, promoting their differentiation into proliferative and fibrotic myofibroblasts; these myostatin effects were inhibited by ATA842. In addition, pharmacologic intervention with verteporfin, a YAP1 inhibitor, blocked myostatin-induced transformation of these stem cells in vitro and reduced adventitial fibrosis and neointima in AV fistulas of CKD mice. YAP1 is a key protein in the Hippo signaling pathway and is crucial for muscle development and function by regulating muscle cell growth, differentiation, and regeneration, but its dysregulation can lead to muscle atrophy and fibrosis.⁵ By contrast, its role in vascular health is context-dependent: Although YAP1 supports vascular function by regulating endothelial and smooth muscle cells to maintain vessel integrity, excessive activation or overexpression of YAP1 can lead to vascular fibrosis, increased vessel stiffness, and abnormal remodeling. Wu et al.³ discovered that myostatin-induced YAP1 contributes to harmful AV fistula remodeling, suggesting that verteporfin could serve as a therapeutic agent to promote AV fistula maturation. However, although verteporfin is US Food and Drug Administration–approved for age-related macular degeneration, its safety in kidney failure patients is unknown and inhibiting YAP1 could have unintended side effects on skeletal muscle, highlighting its potential as a double-edged sword.

There are some limitations to the study by Wu et al.³ This study focused on mesenchymal stem cells, but myostatin's potential effects on vascular endothelial and smooth muscle cells that are crucial for AV fistula maturation need to be defined. Additional studies are warranted to investigate the role of myostatin in medial fibrosis, as clinical evidence linking medial fibrosis to AV fistula maturation more than adventitial fibrosis.² It is also essential to confirm the presence of adventitial mesenchymal stem cells and YAP1 in human preaccess veins and fistulas, as well as investigate the relationship between serum myostatin (or other muscle wasting markers) and AV fistula maturation in patients.

Wu et al.³ also suggest that exercise, particularly handgrip exercises, may improve AV fistula outcomes in hemodialysis patients. However, the latest Kidney Disease Outcomes Quality Initiative guidelines in 2019 state that there is inadequate evidence to recommend upper extremity exercise for AV fistula maturation. Nonetheless, this study illuminates the potential role of muscle health and myokines in AV fistula maturation in dialysis patients. Myokines are cytokines and peptides produced by muscle cells (Table 1).⁶ They play a critical role in regulation of muscle mass, metabolism, and overall health. Myostatin negatively regulates muscle growth. On the other hand, follistatin, irisin, and IL-6 (acute effect) promote muscle growth. Aging and sarcopenia increase myostatin levels and decrease follistatin, leading to further muscle atrophy.⁷ Resistance training, in particular, promotes the release of follistatin, irisin, and IL-6, leading to muscle regeneration and hypertrophy.⁸

Table 1.

Local and systemic effects of myokines

Myokine	Local/Systemic Effects
Myostatin	Inhibits muscle growth; elevated levels are associated with aging and sarcopenia
Follistatin	Inhibits myostatin, promotes muscle growth, and enhances hypertrophy and muscle regeneration
IL-6	Inflammatory cytokine; acute increases during exercise may promote muscle hypertrophy but chronic elevation can lead to muscle atrophy
Irisin	Promotes muscle endurance and metabolic health, converts white fat to brown fat, and improves metabolism
IGF-1	Stimulates muscle hypertrophy and satellite cell proliferation
BDNF	Enhances fat oxidation and may influence muscle fiber type composition, and supports brain function and neurogenesis

BDNF, brain-derived neurotrophic factor; IGF-1, insulin-like growth factor-1.

The key to improving muscle health is increased physical activity, with exercises such as resistance training or aerobic endurance training helping to promote the release of beneficial myokines. Although frailty is common in dialysis patients, a meta-analysis of 12 randomized clinical trials involving 791 patients on maintenance dialysis demonstrated home-based exercise interventions improved walking speed (as measured by the 6-minute walk test), aerobic capacity (assessed by peak oxygen consumption), and quality of life (assessed by Short Form Health score).⁹ In a large randomized controlled trial of 1211 hemodialysis patients, combined endurance and resistance exercise training during hemodialysis versus usual care over a period of 12 months significantly improved the 60-second sit-to-stand test.¹⁰

In conclusion, although much remains to be understood before definitive conclusions can be made about the role of muscle wasting in AV fistula maturation failure, this study raises the possibility that resistance training in hemodialysis patients might improve AV fistula maturation.

Supplementary Material

jasn-36-758-s001.pdf ^{(1.3MB, pdf)}

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F104.

Funding

None.

Author Contributions

Conceptualization: Srinivasan Beddhu, Yan-Ting Shiu.

Writing – original draft: Srinivasan Beddhu, Yan-Ting Shiu.

Writing – review & editing: Srinivasan Beddhu, Yan-Ting Shiu.