Sherene Shalhub, Anahita Dua and Susanna Shin (eds.)Hemodialysis Access10.1007/978-3-319-40061-7_28

28. Understanding Intimal Hyperplasia Biology in Hemodialysis Access

Seth T. Purcell^{1, 2}, Shruti Rao¹ and Ruth L. Bush¹

(1)

Deapartment of Surgery, Texas A&M Health Science Center College of Medicine, MS 1359 8447 State Highway 47, HPEB 3060, Bryan, TX, USA

(2)

Baylor Scott & White Healthcare, Temple, TX, USA

Ruth L. Bush

Email: RBush@medicine.tamhsc.edu

Keywords

Intimal hyperplasiaStenosis of arteriovenous fistula or graft

Introduction

The blood vessel wall is made up of three layers: the intima, the media, and the adventitia. Endothelial cells lying on a layer of connective tissue known as the internal elastic lamina make up the intima, the innermost layer. The internal elastic lamina contains collagen type IV, heparin sulfate proteoglycans, and laminin. Vascular smooth muscle cells (SMC) and extracellular matrix (ECM) make up the medial layer, which is supported by the external elastic lamina. Arteries are thicker than veins due to the increased number of SMCs present and due to elastic fibers in the media. The adventitia is comprised of fibroblasts, ECM, and nerves [1]. Thickening of the blood vessel wall, termed intimal hyperplasia, is due to the migration of SMCs from the media to the intimal layer and their subsequent deposition of extracellular matrix into the zone of injury. Endothelial cell activation, platelet aggregation, leukocyte recruitment, and activation of the coagulation cascade prompt SMC migration and proliferation and lead to intimal hyperplasia [1].

Endothelial cells in the intima form a layer and maintain the integrity and proper function of the vessel walls. A healthy endothelium produces nitric oxide (NO) and secretes prostacyclin (PGI2), both of which help inhibit platelet activation, adhesion, and aggregation. NO also has an anti-inflammatory effect, which inhibits cytokine production and expression of adhesion molecules [1]. Endothelial cells play a key role in activating the cascade of events responsible for intimal hyperplasia. Activated or injured endothelial cells release inflammatory mediators that trigger platelet aggregation and recruitment of leukocytes to the area of injury. These cells also now exhibit increased gene and protein level expression of growth factors such as platelet-derived growth factor (PDGF-2), which promote SMC migration and proliferation [2]. SMCs in the media are usually maintained in a quiescent state by the ECM, transforming growth factor-beta (TGFβ), heparin, and heparin-like molecules, which inhibit cell proliferation and migration. Heparin binds fibroblast growth factor and neutralizes its mitogenic effect on SMCs. TGFβ stabilizes the ECM, limiting SMC movement [1]. In response to stimuli from cytokines and mediators released by endothelial cells, SMCs in the media undergo a phenotypic transformation from a quiescent contractile state to a synthetic and motile state [1]. This prompts their migration from the medial layer to the intimal layer. Numerous stimuli and pathways are thought to be involved in this process. Once migrated, SMCs proliferate to form intimal hyperplasia lesions. Mitogens such as PDGF, insulin-like growth factor (IGF-1), thrombin, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), TGFβ, and cytokines IL-1 and IL-6 all play a role in encouraging SMC proliferation [1, 3]. The alpha smooth muscle actin positive cells that comprise intimal lesions are mostly vimentin-positive, desmin-negative myofibroblasts, with additional fibroblasts and other contractile SMCs [4]. Increase in ECM also adds to the mass of the proliferative lesion. Migration and proliferation of SMC result in encroachment into the blood vessel lumen, causing stenosis.

In current surgical practice, there are two main forms of hemodialysis vascular access, the native arteriovenous fistula (AVF) and the polytetrafluoroethylene graft (PTFE). In the most common configuration of an AVF, a surgical anastomosis of the radial or brachial artery to the cephalic vein is performed [5]. The two major complications include an initial failure to mature and a later venous stenosis followed by access thrombosis. Rates of AVF failure to mature of up to 50 % have been reported, lowering the fistula patency rate from 85 % at 1 year and 75 % at 2 years to as low as 43 % [5]. Arteriovenous PTFE grafts are easy to place and ready to use without a maturation period necessary but have extremely high rates of stenosis, thrombosis, and infection [5]. Patency rates are reported to be at 50 % at 1 year, but rates as low as 23 % at 1 year and 4 % at 2 years have also been reported [5]. The pathogenesis of intimal hyperplasia in AVGs is mostly similar to that in AVFs but with a few minor differences. AVFs stenosis is highly influenced by the vasodilator capacity of the vein and the surgical technique used. Also, AVG stenosis includes a layer of macrophages lining the perigraft region, a finding usually not present in AVF [4].

A series of events, including upstream activities responsible for causing vascular injury and downstream measures consisting of the response to the injury, contribute to the pathogenesis of intimal hyperplasia.

Upstream Events in the Pathogenesis of Intimal Hyperplasia

Upstream events in intimal hyperplasia development are the processes responsible for SMC and endothelial cell activation. These include a spectrum of physical injuries as well as milieu which fosters the inflammatory state needed to perpetuate hyperplasia development. One possible etiology neointimal of hyperplasia is trauma to the vessels at the time of surgery. It has been suggested that this may be significant in the case of the AVF, where the vein may be frequently stretched or manipulated [5]. The trauma from needle holes and the presence of the suture itself may also be an impetus for endothelial cell activation.

Hemodynamic shear stress has also been implicated in intimal hyperplasia. The change from laminar flow with its accompanying high shear stress (tangential force of flowing blood) to turbulent flow with low shear stress promotes endothelial cell activation [6]. At baseline the endothelial cell is able to regulate the coagulation cascade; however, with this change in shear stress, angiotensin-converting enzyme activity and angiotensin II levels significantly decrease [7]. The endothelial cell also secretes less NO and TGFβ, both of which are inhibitors of SMC proliferation. Changes in shear stress influence monocyte and leukocyte adhesion and migration to the surfaces of endothelial cells as well as the expression of adhesion molecules by the endothelial cells themselves [8, 9]. The change in compliance between the artery and the vein utilized in the fistula also contributes to shear stress at the site of the fistula. In the case of AVG, the presence of PTFE has been shown to be an attractant of macrophages [10]. These macrophages in turn form a cell layer that covers the surface of the PTFE. They then express PDGF, basic fibroblast growth factor (bFGF), and VEGF. These factors are known instigators of the migration and proliferation of SMCs and endothelial cells, respectively, which then play their biologic parts in the formation of neointimal hyperplasia.

Just as trauma at the time of fistula creation may be an impetus for intimal hyperplasia development, injury to the vessels from repeated dialysis needle punctures may also play a role in beginning the cascade of neointimal hyperplasia development. Accessing the fistula also affects the shear stress for the duration of the session. Additionally, the presence of the access needles could also initiate a foreign body reaction similar to that caused by PTFE [10].

The uremic milieu fostered by renal failure contributes to the inflammatory processes at play in neointimal hyperplasia development. Renal failure has been shown to produce a systemic inflammatory response which increases oxidative stress, coagulation activation, and endothelial dysfunction [11]. This cause of endothelial dysfunction is likely responsible for neointimal hyperplasia development in vessels of chronic kidney disease (CKD) patients. Neointimal hyperplasia has been shown to preexist in patients with stage 4 and 5 CKD up to 1 year prior to AVF creation, although no direct correlation has been made between preexisting hyperplasia and failure of fistula maturation [12].

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