Distinct subsets of T cells and macrophages impact venous remodeling during arteriovenous fistula maturation

Abstract

Patients with end-stage renal failure depend on hemodialysis indefinitely without renal transplantation, requiring a long-term patent vascular access. While the arteriovenous fistula (AVF) remains the preferred vascular access for hemodialysis because of its longer patency and fewer complications compared with other vascular accesses, the primary patency of AVF is only 50-60%, presenting a clinical need for improvement. AVF mature by developing a thickened vascular wall and increased diameter to adapt to arterial blood pressure and flow volume. Inflammation plays a critical role during vascular remodeling and fistula maturation; increased shear stress triggers infiltration of T-cells and macrophages that initiate inflammation, with involvement of several different subsets of T-cells and macrophages. We review the literature describing distinct roles of the various subsets of T-cells and macrophages during vascular remodeling. Immunosuppression with sirolimus or prednisolone reduces neointimal hyperplasia during AVF maturation, suggesting novel approaches to enhance vascular remodeling. However, M2 macrophages and CD4+ T-cells play essential roles during AVF maturation, suggesting that total immunosuppression may suppress adaptive vascular remodeling. Therefore it is likely that regulation of inflammation during fistula maturation will require a balanced approach to coordinate the various inflammatory cell subsets. Advances in immunosuppressive drug development and delivery systems may allow for more targeted regulation of inflammation to improve vascular remodeling and enhance AVF maturation.

Keywords: Arteriovenous fistula; Inflammation; Macrophages; T-cells; Vascular remodeling.

Graphical abstract

Fig 1

Associations between arteriovenous fistula (AVF) remodeling and inflammation. There are two phases of AVF remodeling, the early phase and the late phase. In the early phase, the remodeling AVF develops wall thickening and outward remodeling to become useable for hemodialysis. CD4⁺ T cells contribute to increased blood flow and outward remodeling, whereas M2 macrophages contribute to wall thickening. In the later phase, some AVF develop neointimal hyperplasia and inward remodeling and can eventually become unusable for hemodialysis. Systemic inflammation is associated with poor AVF patency. Macrophages are associated with neointimal hyperplasia. CRP, C-reactive protein.

Fig 2

Associations between CD4⁺ T cells and macrophages. T-helper (Th) 1 cells secrete interferon-γ (IFN-γ) to induce M1 macrophages. M1 macrophages secrete IFN-γ and tumor necrosis factor-α (TNF-α) to promote inflammation. Th2 cells secrete IL-4 to induce M2a macrophages. Regulatory T cells (Treg) secrete interleukin (IL)-10 and transforming growth factor-β (TGF-β) to induce M2a, M2c and M2d macrophages. M2a and M2c macrophages secrete IL-10 and TGF-β to contribute to anti-inflammation, wound healing, and tissue remodeling. M2d secrete vascular endothelial growth factor (VEGF) to promote angiogenesis.

Fig 3

Associations between effector cytokines and venous remodeling. Tumor necrosis factor-α (TNF-α) causes endothelial barrier dysfunction. Tumor necrosis factor receptor (TNFR)-1 signaling promotes neointimal hyperplasia, but TNFR-2 signaling reduces neointimal hyperplasia. Transforming growth factor-β (TGF-β) promotes vascular smooth muscle cell (SMC) proliferation and neointimal hyperplasia. Interleukin (IL)-1 promotes outward remodeling. Inducible nitric oxide synthase (iNOS) decreases neointimal hyperplasia. IL-10 promotes vascular wall thickening. Factors promoting adaptive venous remodeling are shown in blue and factors inhibiting adaptive venous remodeling are shown in red. Factors having both effects on venous remodeling are shown in purple.