Pro-inflammatory and pro-resolving mechanisms in the immunopathology of arteriovenous fistula maturation

ABSTRACT

Introduction: With high rates of arteriovenous fistula (AVF) failure, there is a continued need to predict other factors and mechanisms associated with maturation deficits. Given the central association of inflammation with AVF failure, with neointimal hyperplasia (NIH) as one such mechanism, inflammation must be considered in two endogenous ways, either pro-inflammatory or pro-resolving, resulting in inward or outward vascular remodeling.

Areas covered: This review summarizes and critically evaluates the preclinical and interventional data underlying AVF failure in attempts to elucidate the necessary balance between inflammation and its resolution.

Expert opinion: Understanding the pro-inflammatory and pro-resolving mechanisms underlying inward and outward vascular remodeling and NIH prevention with AVF maturation is a necessary effort to develop key diagnostic and therapeutic interventions towards the ongoing issue of long-term AVF patency. The ability for clinical application has progressed but is limited to the identification of key targets and pathways with little understanding of how they are related synergistically or antagonistically. Likewise, the balance between acute inflammation and pro-resolution requires pertinent temporal considerations necessary for timely therapeutic application and predictive measurement.

KEYWORDS:

• Arterio-venous fistula
• inflammation
• neointimal hyperplasia
• outward remodeling
• resolvins

Article highlights

• Major etiology of primary arteriovenous (AVF) failure (60–65%) has been deficits in AVF maturation.

• Human studies have identified a pro-inflammatory profile that is associated with the inability of AVF maturation and connects with neointimal hyperplasia via endothelial dysfunction and inflammatory cell recruitment. From this pro-inflammatory standpoint, studies in experimental animals have aided our mechanistic understanding of AVF failure, implicating means via MMIF, TGF-β1, and TNF-α signaling pathways.

• Defective pro-resolution mechanisms in AVF failure have been noted from human studies, including specialized pro-resolving mediators (SPM) deficiency and the diagnostic potential of late elevations in neutrophil-lymphocyte ratio. Nevertheless, an early local pro-inflammatory response to AVF creation may be necessary for outward remodeling efforts to promote AVF maturation, as speculated with the buildup of SPM precursors and early elevations in NLR upon fistula creation.

• Inflammatory characteristics of the local environment of the AVF, particularly eNOS, is crucial for both NIH prevention and outward vascular remodeling necessary for AVF maturation, as appreciated from the animal studies.

• To move the knowledge of AVF failure further will require temporal and mechanistic understanding of the balance of pro-inflammatory processes without mutual exclusivity to pro-resolution and outward remodeling.

Declaration of interest

The authors have no other relevant affiliations or financial or non-financial involvement with any organization or entity with financial or non-financial interest or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The research work of DK Agrawal is supported by research grant [R01HL144125] award from the National Institutes of Health, USA. The content of this review article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health