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Mechanisms underlying vascular access dysfunction
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 4, No. 3 2007
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Cardiovascular diseases MECHANISMS
Mechanisms underlying vascular access dysfunction Amy Mangrum1,*, Mark D. Okusa1,2 1 2
Division of Nephrology, University of Virginia, Box 800133, Charlottesville, VA 22908, USA Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Box 800133, Charlottesville, VA 22908, USA
Vascular access dysfunction remains the Achilles heel of dialysis (D), representing a challenging clinical problem. The primary patency rates are suboptimal and
Section Editor: Joel Linden – Department of Medicine, University of Virginia, Charlottesville, VA, USA
restenosis following angioplasty occurs frequently, leading to high morbidity and mortality rates in patients receiving hemodialysis (HD). Although the mechanisms of vascular injury to other organs have been well established, vascular injury leading to vascular access dysfunction in patients on hemodialysis has not. The uremic environment and the injury associated with hemodialysis contribute to the pathogenesis of vascular access dysfunction. This review summarizes recent literature on the mechanisms of injury leading to vascular access dysfunction. Vascular access dysfunction: the ‘Achilles heel’ of dialysis End-stage renal disease is an irreversible, severe kidney failure for which patients require treatment with dialysis or kidney transplantation to survive. Dialysis (D) is a procedure used to remove metabolic waste products from the blood, which is usually started when a patient’s kidney function is not sufficient enough to clear the body waste products and excess fluid from the body. Hemodialysis (HD) is a procedure that uses a semipermeable membrane to remove the waste products, but not serum proteins and blood cells. The HD machine replaces the work of the failing kidneys. HD requires reliable, repeated access to the patient’s circulation that can *Corresponding author 1740-6765/$ Published by Elsevier Ltd.
DOI: 10.1016/j.ddmec.2008.02.007
provide blood flows of 250–400 mL/min. The superficial venous circulation in the forearm is inadequate for this purpose because the vessels are too small to sustain the high blood flow rates required by the HD machine. One option to achieve such large volume and flow of blood is through creating a direct anastomosis between an artery and a superficial vein in the patient’s arm called the arteriovenous (AV) fistula. After construction of an AV fistula, the vein dilates and can be used after one to three months when it is large enough to hold two 15G needles for the purpose of hemodialysis [1–3]. However, for those patients with unsuitable veins for creating an AV fistula, synthetic material is used to connect an artery to a vein in the arm called an AV graft. Finally, if an AV fistula or graft is not an option and immediate access or short term dialysis is needed, a large double lumen catheter is tunneled underneath the skin and is placed at the junction of superior vena cava and the right atrium to provide the high flow rate of blood required for hemodialysis. Of the three methods of providing vascular access, an AV fistula is the most desirable (type of vascular access) for hemodialysis patients, compared with synthetic grafts and catheters [3]. The single most important reason for vascular access dysfunction is stenosis or occlusion of the vessel at the graft–vein junction or in the venous portion of an AV fistula [3,4]. Rapid diagnosis of a stenotic vascular access is important, re-establishing optimal blood flow to a vascular access is essential. 147
Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases
Vol. 4, No. 3 2007
Figure 1. Vascular access dysfunction. The vascular response to injury in hemodialysis patients is a result of multiple and repeated insults to the vasculature: mechanical injury (initial surgical AV fistula formation or treatment with vascular reconstruction or balloon angioplasty resulting in endothelial damage); proliferative response (neointimal hyperplasia due to the proliferation and migration of medial and intimal VSMC); remodeling (pathological adaptation, increased turnover of the extracellular matrix proteins, increased matrix and metalloproteinase activity); thrombosis (formation of thrombi due to local hemorrhage, thrombosis and stenosis). Additionally, factors unique to HD patients include dialysis needle insertion three times per week (repeated trauma), changes in blood flow pattern and turbulent blood flow in the AV fistula during the dialysis procedure, and the accumulation of metabolic toxins between treatment sessions promotes continued vascular dysfunction on a repetitive basis.
The major complications associated with grafts or AV fistulas are thrombosis, infection, poor clearance of waste products and volume overload. However, a clinical dilemma arises in attempting to diagnose and repair vascular access stenosis [5]. First, in diagnosing the stenosis, an angiogram with radiocontrast agents can lead to vascular injury, recurrent stenosis or thrombosis [6] Second, the repair of the stenotic vessel either by surgical manipulation or dilatation of a stenotic vessel with a balloon (percutaneous balloon angioplasty, PTA) can also lead to vascular injury, which in turn causes further vessel narrowing, resulting in a vicious circle (Fig. 1) [7–11]. Third, one year primary patency rates vary from 50 to 80% when veins or prosthetic grafts are used [10]. During the repair process, after the first angioplasty, the failure rate of an AV fistula or graft at 6 and 12 months is 40 and 60%, respectively, with repeated angioplasty resulting in a further decline in access survival rates and loss [5]. For those reasons, repeated angioplasty is only a temporary measure. Finally, the clinical and economic significance of vascular access dysfunction and repair is shown by the fact that it accounts for about 25% of all hospitalizations of HD patients at a cost of 1 billion dollars/year [7]. Thus, vascular access has been largely considered the ‘Achilles heel’ of dialysis. Improved outcomes require an understanding of the molecular mechanisms unique to vascular access dysfunction in patients requiring HD and are the focus of this review. 148
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Neointimal hyperplasia Surgical creation of the vascular access, even when performed under optimal conditions, is associated with local endothelial injury and denudation [12]. Loss of the endothelial monolayer results in the accumulation of fibrin on the luminal surface, adherence of platelets and neutrophils and a reduction in tissue plasminogen activator (tPA) production [13–15]. Consequently, medial smooth muscle cells (SMC) proliferate in response to the growth factors and cytokines released from the adherent platelets and neutrophils. This is followed by migration of SMC into the intima, with further proliferation as well as extracellular matrix deposition within the intima [15]. This process is called neointimal hyperplasia [5,7,8]. When the lumen becomes narrowed, blood flow through the stenotic lumen is reduced and subsequently, thrombosis and occlusion can occur. Much of our understanding on the molecular mechanisms of AV fistula dysfunction is extrapolated from the literature on coronary artery angioplasty, peripheral vascular reconstruction and coronary artery bypass graft surgery. However, mechanisms mediating vascular wall injury associated with cardiovascular diseases might not accurately reflect mechanisms of vascular wall injury associated with AV fistulas [16]. First, the primary disease process with coronary artery occlusion is atherosclerosis. The primary lesion with AV fistula dysfunction is hyperplasia, as a result of surgery [7]. Second, unlike coronary arteries, AV fistulas are regularly manipu-
Vol. 4, No. 3 2007
lated over time. Dialysis needle insertion three times per week and changes in flow patterns in the AV fistula during dialysis lead to inflammation and neointimal hyperplasia compared with undisturbed peripheral AV anastomosis or coronary arteries. Last, in dialysis patients, the accumulation of metabolic toxins between treatment sessions promotes higher vascular smooth muscle cell (VSMC) proliferative activity. As a consequence, problems occurring at each of these levels can have a cumulative negative effect on the overall prevalence of accelerated vascular stenosis.
Uremia-induced endothelial dysfunction When a patient’s kidneys fail, renal function is restored with hemodialysis. HD is performed approximately three times a week, every other day with each dialysis session lasting for several hours a day. Between dialysis sessions (usually 1-2 days), accumulation of urinary waste products in the blood is called uremia. Although there are many ‘uremic toxins,’ several have been described, which induce endothelial dysfunction. One uremic toxin that contributes to endothelial dysfunction is asymmetric dimethylarginine (ADMA). Accumulation of asymmetric dimethylarginine (ADMA) has been found to be partly elevated in hemodialysis patients because it is excreted via the kidneys. Elevated ADMA level is an endogenous inhibitor nitric oxide synthase (NOS) that decreases the production of nitric oxide (NO) [18,19]. NO is crucial for vascular tone and cellular trafficking of leukocytes. Even as kidney function is declining, endothelial dysfunction is occurring before access formation due to the accumulation of uremic toxins and is perpetuated by the injury sustained during the vascular reconstruction or repair. Evidence from human resistance arteries mounted on a wire myograph showed uremic patients did not respond well to acetylcholine-induced endothelium-dependent vasodilatation compared with healthy controls[17].
Uremia-induced VSMC proliferation Proliferation and migration of smooth muscle cells is considered to be the primary event in neointimal hyperplasia. In the presence of an adjacent overlying healthy, intact endothelium, VSMC remain in a relatively quiescent state. However, when the endothelium is denuded or damaged, there is a marked proliferation of intimal and medial smooth muscle cells that migrate into the intima creating neointimal hyperplasia [16,20]. In a recent study using stenotic lesions derived from human AV fistulas, higher proliferation indices were found in the subendothelial–intimal area compared with adjacent nonstenotic vessels. Double-labeling with a proliferation marker (Ki-67) and for VSMC (a-SMC) revealed that the subendothelial intimal proliferation consisted predominately of VSMC [21]. In addition, proteins that regulate cell cycle progression are altered in AV fistulas including the cyclin-dependent kinase inhibitors; p21Waf1 was upregulated
Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases
and the cell cycle promoter, CdK2 was downregulated [22]. Furthermore, in the treatment of stenotic veins, angioplasty is associated with a higher cellular proliferation activity in early restenotic lesions of AV fistula [23]. The proliferation, migration and deposition of extracellular matrix (ECM) are orchestrated by a large number of mediators that include cytokines, chemokines and adhesion molecules, found to be elevated in hemodialysis patients. The secretion of platelet-derived growth factor (PDGF) by adherent platelets in the subendothelium has been demonstrated both to increase smooth muscle cell proliferation as well as to promote migration of smooth muscle cells to the intima [24]. In an animal model of carotid injury, infused PDGF-BB produced a 2–3-fold increase in medial smooth muscle cell (SMC) proliferation and 20-fold increase in the intimal thickening and the migration of SMC from the media to the intima during the first 7 days after injury [16]. Patients who experienced AV fistula stenosis had higher serum levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and plasma activator inhibitor (PAI)-1 compared with those who did not. Moreover, IL-6 not only might contribute to neointimal formation but also enhances the endothelial synthesis of PAI-1 (inhibitor of fibrinolysis) [16]. Neointimal thickening with deposition of extracellular matrix (ECM) was demonstrated in vein segments of failed AV fistulas. Furthermore, increased protein expression of transforming growth factor (TGF)-b1 and insulin-like growth factor (IGF)-1 was localized in the neointimal and medial layers of the artery [25]. Taken together, these data suggest that patients on HD have a predisposition to accelerated VSMC proliferation, extracellular matrix deposition and subsequent neointimal hyperplasia and thrombosis.
Uremia-induced inflammation Binding of leukocytes to the vascular endothelium is mediated by the cell surface expression of intracellular adhesion molecule (ICAM)-1 and -2 and vascular cell adhesion molecule (VCAM)-1 [26]. In HD patients, circulating levels of ICAM-1, VCAM-1 and monocyte chemoattractant protein (MCP)-1 are elevated compared with control patients not on HD and further elevated during the treatment session with HD. These observations might be the result of inadequate clearance or enhanced synthesis of the adhesion molecules [26]. In the intimal–medial and adventitia area surrounding the fistula, there was a substantial fraction of proliferating cells in the stenotic lesion, with a predominance of macrophages and endothelial cells. Infiltrating macrophages release cytokines such as TGF-b, basic FGF and PDGF, thereby stimulating neovasculogenesis and proliferation of surrounding smooth muscle cells [27]. Macrophages around the microvessels and in the adventitial tissue are five times higher than that of avascular fields [27]. Thus, the uremic environment increases adhesion molecule www.drugdiscoverytoday.com
149
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expression leading to leukocyte adherence, activation and inflammation.
Endothelial progenitor cells inhibited by uremia In response to endothelial injury, endothelial progenitor cells (EPCs) are derived from the bone marrow and are involved in endothelial repair, maintenance and regeneration [28]. Bone marrow transplantation experiments revealed that mesenchymal cells originating from the bone marrow can contribute to re-endothelialization of grafts and denuded arteries. Cells that express endothelial marker proteins (CD34+/KDR+/vascular endothelial growth factor (VEGF) receptor-2+/CD133+) have been shown to behave as EPCs, although the exact lineage and phenotype is unknown [29]. In patients on HD, Choi et al. demonstrated a decreased number of EPCs compared with nonuremic controls [30]. By contrast, Herbrig et al. showed an elevated number of EPCs but a pronounced impairment of EPC migratory kinetics and decreased adhesion to fibronectin and collagen type IV [31]. The consensus is that uremia is associated with a decreased ability of EPC to migrate and adhere to relevant structures of the extracellular matrix, thereby, limiting endothelial repair and contributing to the endothelial dysfunction in uremic patients. Moreover, when uremia is improved by kidney transplantation, EPC migration and adhesion significantly increased as compared with the pretransplant HD patients [31]. In a mouse model of vascular injury, the injection of EPC was associated with endothelialization of the injured segment of the artery and reduced neointimal proliferation. Nontransplanted EPCinjured vessels had increased neointimal thickness and neointimal and medial formation [19]. Taken together, these data support the concept that EPC play a crucial role in reestablishing endothelial integrity in injured vessels and uremia, thereby inhibiting neointimal hyperplasia [29].
Increased flow conditions in the AV fistula Increases in blood flow after the creation of the AV fistula and during the HD session also play a role in the biological remodeling of the AV fistula [2,3,6]. Wedgwood et al. measured flow rates in the radial artery before and after the creation of an AV fistula. Flow increased from 21.6 20.8 to 208 175 mL/min immediately after operation. Later, in well-developed fistulae, flow rates might ultimately reach values of 600–1200 mL/min [37]. Changes in blood flow rates create shear stress on the endothelial cells, which affects the underlying smooth muscle cells. The normal response in an AV fistula is that the vessel remodels itself to maintain a constant predetermined level of shear stress. However, in areas where there is continuous ongoing flow turbulence, compliance mismatch at the graft/vein anastomosis or continued shear stress causes endothelial injury, SMC hyperplasia and venous stenosis. Under low flow conditions, turbulence and neointimal thickening was more pronounced 150
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Vol. 4, No. 3 2007
than under normal flow conditions [33–35]. Eighty five percent of arteriovenous access failures are caused by outflow stenoses at or near the vein/graft anastomosis, at areas of vein bifurcation or at the site of central venous cannulation [6]. Thus, vascular access flow patterns and the vessels ability to adapt to changes in flow is another factor that results in vascular access dysfunction.
Vascular remodeling by access needle insertions Dialysis needle insertion into the AV fistula is required to facilitate a connection between the vascular system and the hemodialysis machine. Continuous and repeated needle insertions result in the displacement of surrounding tissue and damage to the endothelial lining, accumulation of platelets and increase in tissue thrombosis. Furthermore, increased platelet-derived cytokines such as PDGF and increase in inflammatory infiltrates can lead to increased tissue thickness resulting in increased risk for thrombosis and stenosis, which can continue the vicious cycle of vascular access stenosis and thrombosis (Fig. 1) [1,32,24,33].
Breaking the vicious cycle of vascular access dysfunction The theory that neointimal hyperplasia reflects a response to injury in which known cytokine and growth factors predominate suggests that vascular access stenosis is preventable. Thus, a vicious circle of elevated growth promoting cytokines and growth factors, uremia and endothelial damage leading to increased inflammatory infiltration into the injured fistula contribute to recurrent and pronounced vascular stenotic lesions. There are currently no effective therapies for the prevention or treatment of venous neointimal hyperplasia in dialysis grafts. Animal models (pig and mouse) are being developed and validated to study venous neointimal hyperplasia that is very similar to the human lesion [38,39]. Areas of research include perivascular delivery of drugs such as paclitaxel or dipyridamole directly to the adventitia or drug encoated grafts for sustained delivery are potential means for the prevention of neointimal hyperplasia [32,34,35,40,41]. Vascular access dysfunction continues to be a significant clinical problem leading to considerable morbidity among dialysis patients. Currently, once the stenosis is present, PTA or surgical revision is still the cornerstone of vascular access salvage. However, prevention of vascular access stenosis either at the time of initial surgery or during PTA sessions, during the dialysis session or prospective detection of hemodynamic significant stenosis is at the forefront of research.
Acknowledgements The authors gratefully acknowledge Drs. James K. Roche and Kambiz Kalantarinia (Department of Medicine, University of Virginia) for careful reading of the manuscript and advice.
Vol. 4, No. 3 2007
Drug Discovery Today: Disease Mechanisms | Cardiovascular diseases
References 1 Systems, USRD (2002) 2002 Annual Data Report, National Institutes of Health, National Institutes of Diabetes and Digestive Diseases, Bethesda, MD 2 Allon, M. (2007) Current management of vascular access. Clin. J. Am. Soc. Nephrol. 2, 786–800 3 Allon, M. and Robbin, M.L. (2002) Increasing arteriovenous fistulas in hemodialysis patients: problems and solutions. Kidney Int. 62, 1109–1124 4 Konner, K. et al. (2003) The arteriovenous fistula. J. Am. Soc. Nephrol. 14, 1669–1680 5 Rajan, D.K. et al. (2002) Procedural success and patency after percutaneous treatment of thrombosed autogenous arteriovenous dialysis fistulas. J. Vasc. Interv. Radiol. 13, 1211–1218 6 Schwab, S.J. et al. (1999) Vascular access for hemodialysis. Kidney Int. 55, 2078–2090 7 Roy-Chaudhury, P. et al. (2003) Hemodialysis vascular access dysfunction: from pathophysiology to novel therapies. Blood Purif. 21, 99–110 8 Roy-Chaudhury, P. et al. (2006) Hemodialysis vascular access dysfunction: a cellular and molecular viewpoint. J. Am. Soc. Nephrol. 17, 1112–1127 9 Roy-Chaudhury, P. et al. (2005) Vascular access in hemodialysis: issues, management, and emerging concepts. Cardiol. Clin. 23, 249–273 10 Sivanesan, S. et al. (1999) Sites of stenosis in AV fistulae for haemodialysis access. Nephrol. Dial. Transplant. 14, 118–120 11 Clark, T.W. et al. (2002) Outcome and prognostic factors of restenosis after percutaneous treatment of native hemodialysis fistulas. J. Vasc. Interv. Radiol. 13, 51–59 12 Allaire, E. and Clowes, A.W. (1997) Endothelial cell injury in cardiovascular surgery: the intimal hyperplastic response. Ann. Thorac. Surg. 63, 582–591 13 Roubos, N. et al. (1995) Improved preservation of saphenous vein grafts by the use of glyceryl trinitrate-verapamil solution during harvesting. Circulation 92 (Suppl. 9), II31–II36 14 Verrier, E.D. and Boyle, E.M., Jr (1996) Endothelial cell injury in cardiovascular surgery. Ann. Thorac. Surg. 62, 915–922 15 Nachman, R.L. and Silverstein, R. (1993) Hypercoagulable states. Ann. Intern. Med. 119, 819–827 16 De Marchi, S. et al. (1996) Risk factors for vascular disease and arteriovenous fistula dysfunction in hemodialysis patients. J. Am. Soc. Nephrol. 7, 1169–1177 17 Morris, S.T. et al. (2001) Impaired endothelial function in isolated human uremic resistance arteries. Kidney Int. 60, 1077–1082 18 MacAllister, R.J. et al. (1996) Concentration of dimethyl-L-arginine in the plasma of patients with end-stage renal failure. Nephrol. Dial. Transplant. 11, 2449–2452 19 Kielstein, J.T. et al. (1999) Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J. Am. Soc. Nephrol. 10, 594–600 20 Griese, D.P. et al. (2003) Isolation and transplantation of autologous circulating endothelial cells into denuded vessels and prosthetic grafts: implications for cell-based vascular therapy. Circulation 108, 2710–2715 21 Hofstra, L. et al. (1996) Enhanced cellular proliferation in intact stenotic lesions derived from human arteriovenous fistulas and peripheral
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bypass grafts. Does it correlate with flow parameters? Circulation 94, 1283–1290 de Graaf, R. et al. (2003) Detection of cell-cycle regulators in failed arteriovenous fistulas for haemodialysis. Nephrol. Dial. Transplant. 18, 814–818 Chang, C.J. et al. (2004) Highly increased cell proliferation activity in the restenotic hemodialysis vascular access after percutaneous transluminal angioplasty: implication in prevention of restenosis. Am. J. Kidney Dis. 43, 74–84 Jawien, A. et al. (1992) Platelet-derived growth factor promotes smooth muscle migration and intimal thickening in a rat model of balloon angioplasty. J. Clin. Invest. 89, 507–511 Stracke, S. et al. (2002) Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas. Kidney Int. 61, 1011–1019 Papayianni, A. et al. (2002) Circulating levels of ICAM-1, VCAM-1, and MCP-1 are increased in haemodialysis patients: association with inflammation, dyslipidaemia, and vascular events. Nephrol. Dial. Transplant. 17, 435–441 Rekhter, M. et al. (1993) Cell proliferation in human arteriovenous fistulas used for hemodialysis. Arterioscler Thromb. 13, 609–617 Werner, N. et al. (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N. Engl. J. Med. 353, 999–1007 Urbich, C. and Dimmeler, S. (2004) Endothelial progenitor cells: characterization and role in vascular biology. Circ. Res. 95, 343–353 Choi, J.H. et al. (2004) Decreased number and impaired angiogenic function of endothelial progenitor cells in patients with chronic renal failure. Arterioscler Thromb. Vasc. Biol. 24, 1246–1252 Herbrig, K. et al. (2006) Kidney transplantation substantially improves endothelial progenitor cell dysfunction in patients with end-stage renal disease. Am. J. Transplant. 6, 2922–2928 Kelly, B.S. et al. (2002) Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis. Kidney Int. 62, 2272–2280 Nath, K.A. et al. (2003) Increased venous proinflammatory gene expression and intimal hyperplasia in an aorto-caval fistula model in the rat. Am. J. Pathol. 162, 2079–2090 Li, L. et al. (2007) Cellular and morphological changes during neointimal hyperplasia development in a porcine arteriovenous graft model. Nephrol. Dial. Transplant. 22, 3139–3146 Castier, Y. et al. (2006) Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model. Kidney Int. 70, 315–320 Wedgwood, K.R. et al. A prospective study of end-to-side vs. side-to-side arteriovenous fistulas for haemodialysis. Br. J. Surg. 71, 640–642 Castier, Y. et al. (2006) Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model. Kidney Int. 66, 2061–2069 Burnett, S. et al. (2002) Aggressive venous neointimal hyperplasia in a pig model of arteriovenous graft stenosis. Kidney Int. 62, 2272–2280 Masaki, T. et al. (2004) Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel. Kidney Int. 66, 2061– 2069 Himmelfarb, J. et al. (1997) Dipyridamole inhibits PDGF- and bFGFinduced vascular smooth muscle cell proliferation. Kidney Int. 52, 1671– 1677
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151
DRUG DISCOVERY
TODAY
Vol. 4, No. 3 2007
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Charles Lowenstein – The John Hopkins School of Medicine, Baltimore, USA
DISEASE Cardiovascular diseases MECHANISMS
Mechanisms underlying vascular access dysfunction Amy Mangrum1,*, Mark D. Okusa1,2 1 2
Division of Nephrology, University of Virginia, Box 800133, Charlottesville, VA 22908, USA Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Box 800133, Charlottesville, VA 22908, USA
Vascular access dysfunction remains the Achilles heel of dialysis (D), representing a challenging clinical problem. The primary patency rates are suboptimal and
Section Editor: Joel Linden – Department of Medicine, University of Virginia, Charlottesville, VA, USA
restenosis following angioplasty occurs frequently, leading to high morbidity and mortality rates in patients receiving hemodialysis (HD). Although the mechanisms of vascular injury to other organs have been well established, vascular injury leading to vascular access dysfunction in patients on hemodialysis has not. The uremic environment and the injury associated with hemodialysis contribute to the pathogenesis of vascular access dysfunction. This review summarizes recent literature on the mechanisms of injury leading to vascular access dysfunction. Vascular access dysfunction: the ‘Achilles heel’ of dialysis End-stage renal disease is an irreversible, severe kidney failure for which patients require treatment with dialysis or kidney transplantation to survive. Dialysis (D) is a procedure used to remove metabolic waste products from the blood, which is usually started when a patient’s kidney function is not sufficient enough to clear the body waste products and excess fluid from the body. Hemodialysis (HD) is a procedure that uses a semipermeable membrane to remove the waste products, but not serum proteins and blood cells. The HD machine replaces the work of the failing kidneys. HD requires reliable, repeated access to the patient’s circulation that can *Corresponding author 1740-6765/$ Published by Elsevier Ltd.
DOI: 10.1016/j.ddmec.2008.02.007
provide blood flows of 250–400 mL/min. The superficial venous circulation in the forearm is inadequate for this purpose because the vessels are too small to sustain the high blood flow rates required by the HD machine. One option to achieve such large volume and flow of blood is through creating a direct anastomosis between an artery and a superficial vein in the patient’s arm called the arteriovenous (AV) fistula. After construction of an AV fistula, the vein dilates and can be used after one to three months when it is large enough to hold two 15G needles for the purpose of hemodialysis [1–3]. However, for those patients with unsuitable veins for creating an AV fistula, synthetic material is used to connect an artery to a vein in the arm called an AV graft. Finally, if an AV fistula or graft is not an option and immediate access or short term dialysis is needed, a large double lumen catheter is tunneled underneath the skin and is placed at the junction of superior vena cava and the right atrium to provide the high flow rate of blood required for hemodialysis. Of the three methods of providing vascular access, an AV fistula is the most desirable (type of vascular access) for hemodialysis patients, compared with synthetic grafts and catheters [3]. The single most important reason for vascular access dysfunction is stenosis or occlusion of the vessel at the graft–vein junction or in the venous portion of an AV fistula [3,4]. Rapid diagnosis of a stenotic vascular access is important, re-establishing optimal blood flow to a vascular access is essential. 147
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Vol. 4, No. 3 2007
Figure 1. Vascular access dysfunction. The vascular response to injury in hemodialysis patients is a result of multiple and repeated insults to the vasculature: mechanical injury (initial surgical AV fistula formation or treatment with vascular reconstruction or balloon angioplasty resulting in endothelial damage); proliferative response (neointimal hyperplasia due to the proliferation and migration of medial and intimal VSMC); remodeling (pathological adaptation, increased turnover of the extracellular matrix proteins, increased matrix and metalloproteinase activity); thrombosis (formation of thrombi due to local hemorrhage, thrombosis and stenosis). Additionally, factors unique to HD patients include dialysis needle insertion three times per week (repeated trauma), changes in blood flow pattern and turbulent blood flow in the AV fistula during the dialysis procedure, and the accumulation of metabolic toxins between treatment sessions promotes continued vascular dysfunction on a repetitive basis.
The major complications associated with grafts or AV fistulas are thrombosis, infection, poor clearance of waste products and volume overload. However, a clinical dilemma arises in attempting to diagnose and repair vascular access stenosis [5]. First, in diagnosing the stenosis, an angiogram with radiocontrast agents can lead to vascular injury, recurrent stenosis or thrombosis [6] Second, the repair of the stenotic vessel either by surgical manipulation or dilatation of a stenotic vessel with a balloon (percutaneous balloon angioplasty, PTA) can also lead to vascular injury, which in turn causes further vessel narrowing, resulting in a vicious circle (Fig. 1) [7–11]. Third, one year primary patency rates vary from 50 to 80% when veins or prosthetic grafts are used [10]. During the repair process, after the first angioplasty, the failure rate of an AV fistula or graft at 6 and 12 months is 40 and 60%, respectively, with repeated angioplasty resulting in a further decline in access survival rates and loss [5]. For those reasons, repeated angioplasty is only a temporary measure. Finally, the clinical and economic significance of vascular access dysfunction and repair is shown by the fact that it accounts for about 25% of all hospitalizations of HD patients at a cost of 1 billion dollars/year [7]. Thus, vascular access has been largely considered the ‘Achilles heel’ of dialysis. Improved outcomes require an understanding of the molecular mechanisms unique to vascular access dysfunction in patients requiring HD and are the focus of this review. 148
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Neointimal hyperplasia Surgical creation of the vascular access, even when performed under optimal conditions, is associated with local endothelial injury and denudation [12]. Loss of the endothelial monolayer results in the accumulation of fibrin on the luminal surface, adherence of platelets and neutrophils and a reduction in tissue plasminogen activator (tPA) production [13–15]. Consequently, medial smooth muscle cells (SMC) proliferate in response to the growth factors and cytokines released from the adherent platelets and neutrophils. This is followed by migration of SMC into the intima, with further proliferation as well as extracellular matrix deposition within the intima [15]. This process is called neointimal hyperplasia [5,7,8]. When the lumen becomes narrowed, blood flow through the stenotic lumen is reduced and subsequently, thrombosis and occlusion can occur. Much of our understanding on the molecular mechanisms of AV fistula dysfunction is extrapolated from the literature on coronary artery angioplasty, peripheral vascular reconstruction and coronary artery bypass graft surgery. However, mechanisms mediating vascular wall injury associated with cardiovascular diseases might not accurately reflect mechanisms of vascular wall injury associated with AV fistulas [16]. First, the primary disease process with coronary artery occlusion is atherosclerosis. The primary lesion with AV fistula dysfunction is hyperplasia, as a result of surgery [7]. Second, unlike coronary arteries, AV fistulas are regularly manipu-
Vol. 4, No. 3 2007
lated over time. Dialysis needle insertion three times per week and changes in flow patterns in the AV fistula during dialysis lead to inflammation and neointimal hyperplasia compared with undisturbed peripheral AV anastomosis or coronary arteries. Last, in dialysis patients, the accumulation of metabolic toxins between treatment sessions promotes higher vascular smooth muscle cell (VSMC) proliferative activity. As a consequence, problems occurring at each of these levels can have a cumulative negative effect on the overall prevalence of accelerated vascular stenosis.
Uremia-induced endothelial dysfunction When a patient’s kidneys fail, renal function is restored with hemodialysis. HD is performed approximately three times a week, every other day with each dialysis session lasting for several hours a day. Between dialysis sessions (usually 1-2 days), accumulation of urinary waste products in the blood is called uremia. Although there are many ‘uremic toxins,’ several have been described, which induce endothelial dysfunction. One uremic toxin that contributes to endothelial dysfunction is asymmetric dimethylarginine (ADMA). Accumulation of asymmetric dimethylarginine (ADMA) has been found to be partly elevated in hemodialysis patients because it is excreted via the kidneys. Elevated ADMA level is an endogenous inhibitor nitric oxide synthase (NOS) that decreases the production of nitric oxide (NO) [18,19]. NO is crucial for vascular tone and cellular trafficking of leukocytes. Even as kidney function is declining, endothelial dysfunction is occurring before access formation due to the accumulation of uremic toxins and is perpetuated by the injury sustained during the vascular reconstruction or repair. Evidence from human resistance arteries mounted on a wire myograph showed uremic patients did not respond well to acetylcholine-induced endothelium-dependent vasodilatation compared with healthy controls[17].
Uremia-induced VSMC proliferation Proliferation and migration of smooth muscle cells is considered to be the primary event in neointimal hyperplasia. In the presence of an adjacent overlying healthy, intact endothelium, VSMC remain in a relatively quiescent state. However, when the endothelium is denuded or damaged, there is a marked proliferation of intimal and medial smooth muscle cells that migrate into the intima creating neointimal hyperplasia [16,20]. In a recent study using stenotic lesions derived from human AV fistulas, higher proliferation indices were found in the subendothelial–intimal area compared with adjacent nonstenotic vessels. Double-labeling with a proliferation marker (Ki-67) and for VSMC (a-SMC) revealed that the subendothelial intimal proliferation consisted predominately of VSMC [21]. In addition, proteins that regulate cell cycle progression are altered in AV fistulas including the cyclin-dependent kinase inhibitors; p21Waf1 was upregulated
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and the cell cycle promoter, CdK2 was downregulated [22]. Furthermore, in the treatment of stenotic veins, angioplasty is associated with a higher cellular proliferation activity in early restenotic lesions of AV fistula [23]. The proliferation, migration and deposition of extracellular matrix (ECM) are orchestrated by a large number of mediators that include cytokines, chemokines and adhesion molecules, found to be elevated in hemodialysis patients. The secretion of platelet-derived growth factor (PDGF) by adherent platelets in the subendothelium has been demonstrated both to increase smooth muscle cell proliferation as well as to promote migration of smooth muscle cells to the intima [24]. In an animal model of carotid injury, infused PDGF-BB produced a 2–3-fold increase in medial smooth muscle cell (SMC) proliferation and 20-fold increase in the intimal thickening and the migration of SMC from the media to the intima during the first 7 days after injury [16]. Patients who experienced AV fistula stenosis had higher serum levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and plasma activator inhibitor (PAI)-1 compared with those who did not. Moreover, IL-6 not only might contribute to neointimal formation but also enhances the endothelial synthesis of PAI-1 (inhibitor of fibrinolysis) [16]. Neointimal thickening with deposition of extracellular matrix (ECM) was demonstrated in vein segments of failed AV fistulas. Furthermore, increased protein expression of transforming growth factor (TGF)-b1 and insulin-like growth factor (IGF)-1 was localized in the neointimal and medial layers of the artery [25]. Taken together, these data suggest that patients on HD have a predisposition to accelerated VSMC proliferation, extracellular matrix deposition and subsequent neointimal hyperplasia and thrombosis.
Uremia-induced inflammation Binding of leukocytes to the vascular endothelium is mediated by the cell surface expression of intracellular adhesion molecule (ICAM)-1 and -2 and vascular cell adhesion molecule (VCAM)-1 [26]. In HD patients, circulating levels of ICAM-1, VCAM-1 and monocyte chemoattractant protein (MCP)-1 are elevated compared with control patients not on HD and further elevated during the treatment session with HD. These observations might be the result of inadequate clearance or enhanced synthesis of the adhesion molecules [26]. In the intimal–medial and adventitia area surrounding the fistula, there was a substantial fraction of proliferating cells in the stenotic lesion, with a predominance of macrophages and endothelial cells. Infiltrating macrophages release cytokines such as TGF-b, basic FGF and PDGF, thereby stimulating neovasculogenesis and proliferation of surrounding smooth muscle cells [27]. Macrophages around the microvessels and in the adventitial tissue are five times higher than that of avascular fields [27]. Thus, the uremic environment increases adhesion molecule www.drugdiscoverytoday.com
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expression leading to leukocyte adherence, activation and inflammation.
Endothelial progenitor cells inhibited by uremia In response to endothelial injury, endothelial progenitor cells (EPCs) are derived from the bone marrow and are involved in endothelial repair, maintenance and regeneration [28]. Bone marrow transplantation experiments revealed that mesenchymal cells originating from the bone marrow can contribute to re-endothelialization of grafts and denuded arteries. Cells that express endothelial marker proteins (CD34+/KDR+/vascular endothelial growth factor (VEGF) receptor-2+/CD133+) have been shown to behave as EPCs, although the exact lineage and phenotype is unknown [29]. In patients on HD, Choi et al. demonstrated a decreased number of EPCs compared with nonuremic controls [30]. By contrast, Herbrig et al. showed an elevated number of EPCs but a pronounced impairment of EPC migratory kinetics and decreased adhesion to fibronectin and collagen type IV [31]. The consensus is that uremia is associated with a decreased ability of EPC to migrate and adhere to relevant structures of the extracellular matrix, thereby, limiting endothelial repair and contributing to the endothelial dysfunction in uremic patients. Moreover, when uremia is improved by kidney transplantation, EPC migration and adhesion significantly increased as compared with the pretransplant HD patients [31]. In a mouse model of vascular injury, the injection of EPC was associated with endothelialization of the injured segment of the artery and reduced neointimal proliferation. Nontransplanted EPCinjured vessels had increased neointimal thickness and neointimal and medial formation [19]. Taken together, these data support the concept that EPC play a crucial role in reestablishing endothelial integrity in injured vessels and uremia, thereby inhibiting neointimal hyperplasia [29].
Increased flow conditions in the AV fistula Increases in blood flow after the creation of the AV fistula and during the HD session also play a role in the biological remodeling of the AV fistula [2,3,6]. Wedgwood et al. measured flow rates in the radial artery before and after the creation of an AV fistula. Flow increased from 21.6 20.8 to 208 175 mL/min immediately after operation. Later, in well-developed fistulae, flow rates might ultimately reach values of 600–1200 mL/min [37]. Changes in blood flow rates create shear stress on the endothelial cells, which affects the underlying smooth muscle cells. The normal response in an AV fistula is that the vessel remodels itself to maintain a constant predetermined level of shear stress. However, in areas where there is continuous ongoing flow turbulence, compliance mismatch at the graft/vein anastomosis or continued shear stress causes endothelial injury, SMC hyperplasia and venous stenosis. Under low flow conditions, turbulence and neointimal thickening was more pronounced 150
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than under normal flow conditions [33–35]. Eighty five percent of arteriovenous access failures are caused by outflow stenoses at or near the vein/graft anastomosis, at areas of vein bifurcation or at the site of central venous cannulation [6]. Thus, vascular access flow patterns and the vessels ability to adapt to changes in flow is another factor that results in vascular access dysfunction.
Vascular remodeling by access needle insertions Dialysis needle insertion into the AV fistula is required to facilitate a connection between the vascular system and the hemodialysis machine. Continuous and repeated needle insertions result in the displacement of surrounding tissue and damage to the endothelial lining, accumulation of platelets and increase in tissue thrombosis. Furthermore, increased platelet-derived cytokines such as PDGF and increase in inflammatory infiltrates can lead to increased tissue thickness resulting in increased risk for thrombosis and stenosis, which can continue the vicious cycle of vascular access stenosis and thrombosis (Fig. 1) [1,32,24,33].
Breaking the vicious cycle of vascular access dysfunction The theory that neointimal hyperplasia reflects a response to injury in which known cytokine and growth factors predominate suggests that vascular access stenosis is preventable. Thus, a vicious circle of elevated growth promoting cytokines and growth factors, uremia and endothelial damage leading to increased inflammatory infiltration into the injured fistula contribute to recurrent and pronounced vascular stenotic lesions. There are currently no effective therapies for the prevention or treatment of venous neointimal hyperplasia in dialysis grafts. Animal models (pig and mouse) are being developed and validated to study venous neointimal hyperplasia that is very similar to the human lesion [38,39]. Areas of research include perivascular delivery of drugs such as paclitaxel or dipyridamole directly to the adventitia or drug encoated grafts for sustained delivery are potential means for the prevention of neointimal hyperplasia [32,34,35,40,41]. Vascular access dysfunction continues to be a significant clinical problem leading to considerable morbidity among dialysis patients. Currently, once the stenosis is present, PTA or surgical revision is still the cornerstone of vascular access salvage. However, prevention of vascular access stenosis either at the time of initial surgery or during PTA sessions, during the dialysis session or prospective detection of hemodynamic significant stenosis is at the forefront of research.
Acknowledgements The authors gratefully acknowledge Drs. James K. Roche and Kambiz Kalantarinia (Department of Medicine, University of Virginia) for careful reading of the manuscript and advice.
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