Novel Paradigms for Dialysis Vascular Access: Introduction Michael Allon
Clin J Am Soc Nephrol 8: 2183–2185, 2013. doi: 10.2215/CJN.03650413
Nonmaturation of new arteriovenous fistulas (AVFs) remains a major barrier to increasing AVF use in hemodialysis patients (1). Our current clinical paradigm views nonmaturing AVF as a plumbing problem, with efforts directed at augmenting access flow by surgical or percutaneous interventions (2–4). Unfortunately, the very same interventions utilized to salvage immature fistulas also result in vascular injury, which in turn promotes recurrent intimal hyperplasia, rapid re-stenosis, shortened cumulative AVF survival, and the need for frequent interventions to maintain longterm AVF patency for dialysis (5,6). Vascular access research in humans and experimental models reported in the past few years highlights the complex biologic factors involved in AVF nonmaturation. These studies raise the exciting potential of identifying specific pharmacologic interventions to promote AVF maturation. A symposium held at the 2012 American Society of Nephrology Kidney Week in San Diego, California, highlighted new paradigms in our understanding of the mechanisms of AVF nonmaturation, and their implications for prevention of this problem. We invited the speakers at that symposium to amplify on their lectures for this Moving Points in Nephrology collection. Our current understanding of the pathogenesis of AVF nonmaturation distinguishes between upstream and downstream events (7). “Upstream events” result in the initial vascular injury, which in turn produces “downstream events” (a biologic response to the initial injury leading to neointimal hyperplasia, stenosis, and ultimately AVF failure) (Figure 1). The initial injury may be caused by surgical injury to the vessels during AVF creation, as well as hemodynamic shear stress near the anastomotic site. The magnitude of vascular injury and the resultant biologic response is likely modified by numerous factors, including genetic predisposition, uremia, and preexisting vascular pathology. Creation of an AVF results in a nonphysiologic condition whereby the low-pressure vein is exposed to the high-pressure artery, resulting in shear stress and vascular injury. The shear stress in a new AVF is not evenly distributed. Rather, it is localized to the juxtaanastomotic region (within approximately 2 cm of the artery-vein anastomosis). Imaging studies of nonmaturing AVF typically demonstrate focal stenosis in the juxta-anastomotic region (2,3). Most vascular www.cjasn.org Vol 8 December, 2013
surgeons create the anastomosis with a 90° angle between the vein and the artery. Elegant computational modeling of radiocephalic AVF has demonstrated disturbed flow at the swing segment of the vein and in the arterial segment proximal to the anastomosis (8). Moreover, varying the angle of the anastomosis in this model dramatically alters the shear stress. As the angle is decreased from 90° to 30°, there is a progressive decrease in shear stress, which may attenuate the vascular injury, neointimal hyperplasia, and development of juxta-anastomotic stenosis (9). The clinical relevance of these experimental findings was supported by a recent observational clinical study, in which changing the anastomotic angle of AVF from 90° to 30° reduced early juxta-anastomotic stenosis from 40% to 10% (10). Similarly, the Optiflow device may decrease vascular injury by fixing the angle at 60° (11). It is unknown whether the shear stress differs between brachiocephalic and radiocephalic AVF, because the former have a considerably lower nonmaturation rate than the latter (12). The article by Dr. Remuzzi amplifies on the relationship between AVF configuration, shear stress, and development of juxta-anastomotic AVF stenosis. Neointimal hyperplasia is the final common pathway in the pathogenesis of juxta-anastomotic AVF stenosis. It develops within 3 weeks in experimental models of AVF (13–16), and has been documented in a small number of hemodialysis patients who underwent surgical revision due to AVF nonmaturation 2–6 months after their initial AVF creation (17,18). Experimental models have evaluated the role of some specific mediators in regulating neointimal hyperplasia after AVF creation. The initial biologic response to injury entails migration of myofibroblasts and smooth muscle cells from the adventitia and media into the intima, leading to subsequent aggressive neointimal hyperplasia (7). Numerous regulators mediate or modulate this biologic response, including cell cycle regulators, cytokines, chemokines, vasoactive molecules, adhesion molecules, and metallic matrix proteinases. For example, heme oxygenase-1 (HO-1) has antiproliferative properties. HO-1 knockout mice exhibit accelerated neointimal hyperplasia of their AVF, highlighting the physiologic role of HO-1 in attenuating neointimal hyperplasia (13). The clinical relevance of these experimental findings was demonstrated by
Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama Correspondence: Dr. Michael Allon, Division of Nephrology, University of Alabama at Birmingham, PB, Room 226, 1530 Third Avenue South, Birmingham, AL 35294. Email: [email protected]
Copyright © 2013 by the American Society of Nephrology
2183
2184
Clinical Journal of the American Society of Nephrology
Figure 1. | Pathogenesis of arteriovenous fistula (AVF) nonmaturation.
an observational study from Taiwan, which evaluated the association of AVF survival with HO-1 length polymorphisms in hemodialysis patients (19). A promoter gene regulates the transcription of HO-1. G-T length polymorphisms of this promoter affect HO-1 expression. The L/L genotype (longer GT repeats) is associated with a lower rate of HO-1 transcription than the S/S genotype (shorter GT repeats). Compared with the patients with the S/S genotype, those with the L/L genotype have shorter AVF patency. More recent research has focused on preexisting vascular pathology in hemodialysis patients, and its potential contribution to the pathogenesis of neointimal hyperplasia in new AVFs. Several arterial and venous abnormalities have been described in patients undergoing vascular access creation, including venous intimal hyperplasia, arterial intimal hyperplasia, arterial medial fibrosis, arterial calcification, and venous calcification (18,20–23). A plausible hypothesis is that preexisting vascular pathology predisposes to accelerated neointimal hyperplasia and juxtaanastomotic stenosis in patients receiving a new AVF. A pilot Korean study reported significantly decreased AVF patency in patients with preexisting arterial intimal hyperplasia compared with that observed in patients without this pathology (23). A second study found no association of preexisting arterial medial fibrosis or arterial calcification with AVF nonmaturation (18). In contrast, a third study observed a lower frequency of arteriovenous graft (AVG) interventions in patients with preexisting arterial or venous pathology, suggesting a protective effect against neointimal hyperplasia in vascular access (24). These contradictory findings suggest that the cellular mechanisms leading to neointimal hyperplasia after AVF creation differ from those leading to the preexisting ;vascular abnormalities in uremic patients. Dr. Lee’s article provides a comprehensive overview of the mediators and modulators of neointimal hyperplasia, and the experimental evidence on how they affect AVF maturation. What are the potential pharmacologic interventions to prevent vascular access failure? The only drug that has been evaluated for prevention of AVF nonmaturation is clopidogrel (25). A multicenter randomized clinical trial allocated patients to receive either clopidogrel or placebo for 6 weeks after AVF surgery. The frequency of AVF thrombosis within 6 weeks was significantly lower in patients
receiving clopidogrel (12.2% versus 19.5%; P50.02), but AVF nonmaturation was similar in both groups (61.8% versus 59.5%; P50.40). Four randomized studies have evaluated pharmacologic interventions to prevent AVG failure (stenosis or thrombosis). Neither warfarin nor aspirin 1 clopidogrel prevented AVG thrombosis, but both drug regimens increased the risk of bleeding complications (26,27). Dipyridamole 1 aspirin produced a modest, but significant, prolongation of primary unassisted AVG survival (28). Finally, fish oil decreased the frequency of angioplasty and thrombosis in new AVG (29). Systemic administration requires achieving relatively high blood drug levels in order to ensure sufficient antiproliferative effects at the target site (arteriovenous anastomosis for AVF and venous-graft anastomosis for AVG). These high systemic levels may expose the patients to significant adverse effects. There has been considerable interest in devising local drug delivery systems that would achieve a high drug level at the target site, while minimizing the risk of systemic drug toxicity (30). Potential local drug delivery systems, such as topical administration, adventitial wraps, cell implants, and gene delivery systems, have been evaluated in animal models. A limited number of phase 1/2 clinical trials have tested such therapies in dialysis patients. These pilot studies have included allogeneic endothelial cell implants (31), sirolimus-eluting collagen membranes (32), and pancreatic elastase (33). These small studies demonstrated the feasibility and safety of a variety of local drug delivery systems. However, large multicenter randomized clinical trials will be required to evaluate the clinical efficacy of these interventions in preventing vascular access failure. Drs. Terry and Dember have written a comprehensive review of new pharmacologic therapies in the horizon that may improve vascular access outcomes. Acknowledgments This manuscript was supported by funding from a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (R01-DK-085027) to Dr. Allon. Disclosures None. References 1. Allon M: Current management of vascular access. Clin J Am Soc Nephrol 2: 786–800, 2007 2. Beathard GA, Arnold P, Jackson J, Litchfield T; Physician Operators Forum of RMS Lifeline: Aggressive treatment of early fistula failure. Kidney Int 64: 1487–1494, 2003 3. Asif A, Lenz O, Merrill D, Cherla G, Cipleu CD, Ellis R, Francois B, Epstein DL, Pennell P: Percutaneous management of perianastomotic stenosis in arteriovenous fistulae: Results of a prospective study. Kidney Int 69: 1904–1909, 2006 4. Turmel-Rodrigues L, Mouton A, Birmele´ B, Billaux L, Ammar N, Gre´zard O, Hauss S, Pengloan J: Salvage of immature forearm fistulas for haemodialysis by interventional radiology. Nephrol Dial Transplant 16: 2365–2371, 2001 5. Chang CJ, Ko PJ, Hsu LA, Ko YS, Ko YL, Chen CF, Huang CC, Hsu TS, Lee YS, Pang JH: 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, 2004 6. Lee T, Ullah A, Allon M, Succop P, El-Khatib M, Munda R, RoyChaudhury P: Decreased cumulative access survival in
Clin J Am Soc Nephrol 8: 2183–2185, December, 2013
7. 8.
9.
10. 11.
12. 13.
14. 15.
16. 17. 18.
19.
20.
21.
22.
23.
arteriovenous fistulas requiring interventions to promote maturation. Clin J Am Soc Nephrol 6: 575–581, 2011 Roy-Chaudhury P, Sukhatme VP, Cheung AK: Hemodialysis vascular access dysfunction: A cellular and molecular viewpoint. J Am Soc Nephrol 17: 1112–1127, 2006 Ene-Iordache B, Remuzzi A: Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: Low and oscillating shear stress locates the sites of stenosis. Nephrol Dial Transplant 27: 358–368, 2012 Ene-Iordache B, Cattaneo L, Dubini G, Remuzzi A: Effect of anastomosis angle on the localization of disturbed flow in ‘sideto-end’ fistulae for haemodialysis access. Nephrol Dial Transplant 28: 997–1005, 2013 Bharat A, Jaenicke M, Shenoy S: A novel technique of vascular anastomosis to prevent juxta-anastomotic stenosis following arteriovenous fistula creation. J Vasc Surg 55: 274–280, 2012 Manson RJ, Ebner A, Gallo S, Chemla E, Mantell MP, Deaton D, Roy-Chaudhury P: Arteriovenous fistula creation using the Optiflow vascular anastomosis device: A first in man pilot study. Semin Dial 26: 97–99, 2013 Peterson WJ, Barker J, Allon M: Disparities in fistula maturation persist despite preoperative vascular mapping. Clin J Am Soc Nephrol 3: 437–441, 2008 Juncos JP, Tracz MJ, Croatt AJ, Grande JP, Ackerman AW, Katusic ZS, Nath KA: Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse. Kidney Int 74: 47–51, 2008 Juncos JP, Grande JP, Kang L, Ackerman AW, Croatt AJ, Katusic ZS, Nath KA: MCP-1 contributes to arteriovenous fistula failure. J Am Soc Nephrol 22: 43–48, 2011 Langer S, Kokozidou M, Heiss C, Kranz J, Kessler T, Paulus N, Kru¨ger T, Jacobs MJ, Lente C, Koeppel TA: Chronic kidney disease aggravates arteriovenous fistula damage in rats. Kidney Int 78: 1312–1321, 2010 Castier Y, Lehoux S, Hu Y, Foteinos G, Tedgui A, Xu Q: Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model. Kidney Int 70: 315–320, 2006 Roy-Chaudhury P, Arend L, Zhang J, Krishnamoorthy MS, Wang Y, Banerjee R, Samaha A, Munda R: Neointimal hyperplasia in early arteriovenous fistula failure. Am J Kidney Dis 50: 782–790, 2007 Allon M, Litovsky S, Young CJ, Deierhoi MH, Goodman J, Hanaway M, Lockhart ME, Robbin ML: Medial fibrosis, vascular calcification, intimal hyperplasia, and arteriovenous fistula maturation. Am J Kidney Dis 58: 437–443, 2011 Lin CC, Yang WC, Lin SJ, Chen TW, Lee WS, Chang CF, Lee PC, Lee SD, Su TS, Fann CS, Chung MY: Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients. Kidney Int 69: 165–172, 2006 Lee TC, Chauhan V, Krishnamoorthy M, Wang Y, Arend L, Mistry MJ, El-Khatib M, Banerjee R, Munda R, Roy-Chaudhury P: Severe venous neointimal hyperplasia prior to dialysis access surgery. Nephrol Dial Transplant 26: 2264–2270, 2011 Lee T, Safdar N, Mistry MJ, Wang Y, Chauhan V, Campos B, Munda R, Cornea V, Roy-Chaudhury P: Preexisting venous calcification prior to dialysis vascular access surgery. Semin Dial 25: 592–595, 2012 Wasse H, Rivera AA, Huang R, Martinson DE, Long Q, McKinnon W, Naqvi N, Husain A: Increased plasma chymase concentration and mast cell chymase expression in venous neointimal lesions of patients with CKD and ESRD. Semin Dial 24: 688–693, 2011 Kim YO, Song HC, Yoon SA, Yang CW, Kim NI, Choi YJ, Lee EJ, Kim WY, Chang YS, Bang BK: Preexisting intimal hyperplasia of radial artery is associated with early failure of radiocephalic
Novel Paradigms for Dialysis Vascular Access, Allon
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25.
26.
27.
28.
29.
30. 31.
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33.
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arteriovenous fistula in hemodialysis patients. Am J Kidney Dis 41: 422–428, 2003 Allon M, Litovsky S, Young CJ, Deierhoi MH, Goodman J, Hanaway M, Lockhart ME, Robbin ML: Pre-existing vascular pathology correlation with arteriovenous graft outcomes in hemodialysis patients. Am J Kidney Dis 2013, in press Dember LM, Beck GJ, Allon M, Delmez JA, Dixon BS, Greenberg A, Himmelfarb J, Vazquez MA, Gassman JJ, Greene T, Radeva MK, Braden GL, Ikizler TA, Rocco MV, Davidson IJ, Kaufman JS, Meyers CM, Kusek JW, Feldman HI; Dialysis Access Consortium Study Group: Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: A randomized controlled trial. JAMA 299: 2164–2171, 2008 Crowther MA, Clase CM, Margetts PJ, Julian J, Lambert K, Sneath D, Nagai R, Wilson S, Ingram AJ: Low-intensity warfarin is ineffective for the prevention of PTFE graft failure in patients on hemodialysis: A randomized controlled trial. J Am Soc Nephrol 13: 2331–2337, 2002 Kaufman JS, O’Connor TZ, Zhang JH, Cronin RE, Fiore LD, Ganz MB, Goldfarb DS, Peduzzi PN; Veterans Affairs Cooperative Study Group on Hemodialysis Access Graft Thrombosis: Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis. J Am Soc Nephrol 14: 2313–2321, 2003 Dixon BS, Beck GJ, Vazquez MA, Greenberg A, Delmez JA, Allon M, Dember LM, Himmelfarb J, Gassman JJ, Greene T, Radeva MK, Davidson IJ, Ikizler TA, Braden GL, Fenves AZ, Kaufman JS, Cotton JR Jr, Martin KJ, McNeil JW, Rahman A, Lawson JH, Whiting JF, Hu B, Meyers CM, Kusek JW, Feldman HI; DAC Study Group: Effect of dipyridamole plus aspirin on hemodialysis graft patency. N Engl J Med 360: 2191–2201, 2009 Lok CE, Moist LM, Hemmelgarn BR, Tonelli M, Vazquez MA, Dorval M, Oliver M, Donnelly S, Allon M, Stanley K; Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) Study Group: Effect of fish oil supplementation on graft patency and cardiovascular events among patients with new synthetic arteriovenous hemodialysis grafts: A randomized controlled trial. JAMA 307: 1809–1816, 2012 Li L, Terry CM, Shiu YTE, Cheung AK: Neointimal hyperplasia associated with synthetic hemodialysis grafts. Kidney Int 74: 1247–1261, 2008 Conte MS, Nugent HM, Gaccione P, Guleria I, Roy-Chaudhury P, Lawson JH: Multicenter phase I/II trial of the safety of allogeneic endothelial cell implants after the creation of arteriovenous access for hemodialysis use: The V-HEALTH study. J Vasc Surg 50: 1359–1368, e1, 2009 Paulson WD, Kipshidze N, Kipiani K, Beridze N, DeVita MV, Shenoy S, Iyer SS: Safety and efficacy of local periadventitial delivery of sirolimus for improving hemodialysis graft patency: First human experience with a sirolimus-eluting collagen membrane (Coll-R). Nephrol Dial Transplant 27: 1219–1224, 2012 Peden EK, Leeser DB, Dixon BS, El-Khatib MT, Roy-Chaudhury P, Lawson JH, Menard MT, Dember LM, Glickman MH, Gustafson PN, Blair AT, Magill M, Franano FN, Burke SK: A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation [published online ahead of print November 20, 2012]. J Vasc Access doi: 10.5301/jva.5000125
Published online ahead of print. Publication date available at www. cjasn.org.
Clin J Am Soc Nephrol 8: 2183–2185, 2013. doi: 10.2215/CJN.03650413
Nonmaturation of new arteriovenous fistulas (AVFs) remains a major barrier to increasing AVF use in hemodialysis patients (1). Our current clinical paradigm views nonmaturing AVF as a plumbing problem, with efforts directed at augmenting access flow by surgical or percutaneous interventions (2–4). Unfortunately, the very same interventions utilized to salvage immature fistulas also result in vascular injury, which in turn promotes recurrent intimal hyperplasia, rapid re-stenosis, shortened cumulative AVF survival, and the need for frequent interventions to maintain longterm AVF patency for dialysis (5,6). Vascular access research in humans and experimental models reported in the past few years highlights the complex biologic factors involved in AVF nonmaturation. These studies raise the exciting potential of identifying specific pharmacologic interventions to promote AVF maturation. A symposium held at the 2012 American Society of Nephrology Kidney Week in San Diego, California, highlighted new paradigms in our understanding of the mechanisms of AVF nonmaturation, and their implications for prevention of this problem. We invited the speakers at that symposium to amplify on their lectures for this Moving Points in Nephrology collection. Our current understanding of the pathogenesis of AVF nonmaturation distinguishes between upstream and downstream events (7). “Upstream events” result in the initial vascular injury, which in turn produces “downstream events” (a biologic response to the initial injury leading to neointimal hyperplasia, stenosis, and ultimately AVF failure) (Figure 1). The initial injury may be caused by surgical injury to the vessels during AVF creation, as well as hemodynamic shear stress near the anastomotic site. The magnitude of vascular injury and the resultant biologic response is likely modified by numerous factors, including genetic predisposition, uremia, and preexisting vascular pathology. Creation of an AVF results in a nonphysiologic condition whereby the low-pressure vein is exposed to the high-pressure artery, resulting in shear stress and vascular injury. The shear stress in a new AVF is not evenly distributed. Rather, it is localized to the juxtaanastomotic region (within approximately 2 cm of the artery-vein anastomosis). Imaging studies of nonmaturing AVF typically demonstrate focal stenosis in the juxta-anastomotic region (2,3). Most vascular www.cjasn.org Vol 8 December, 2013
surgeons create the anastomosis with a 90° angle between the vein and the artery. Elegant computational modeling of radiocephalic AVF has demonstrated disturbed flow at the swing segment of the vein and in the arterial segment proximal to the anastomosis (8). Moreover, varying the angle of the anastomosis in this model dramatically alters the shear stress. As the angle is decreased from 90° to 30°, there is a progressive decrease in shear stress, which may attenuate the vascular injury, neointimal hyperplasia, and development of juxta-anastomotic stenosis (9). The clinical relevance of these experimental findings was supported by a recent observational clinical study, in which changing the anastomotic angle of AVF from 90° to 30° reduced early juxta-anastomotic stenosis from 40% to 10% (10). Similarly, the Optiflow device may decrease vascular injury by fixing the angle at 60° (11). It is unknown whether the shear stress differs between brachiocephalic and radiocephalic AVF, because the former have a considerably lower nonmaturation rate than the latter (12). The article by Dr. Remuzzi amplifies on the relationship between AVF configuration, shear stress, and development of juxta-anastomotic AVF stenosis. Neointimal hyperplasia is the final common pathway in the pathogenesis of juxta-anastomotic AVF stenosis. It develops within 3 weeks in experimental models of AVF (13–16), and has been documented in a small number of hemodialysis patients who underwent surgical revision due to AVF nonmaturation 2–6 months after their initial AVF creation (17,18). Experimental models have evaluated the role of some specific mediators in regulating neointimal hyperplasia after AVF creation. The initial biologic response to injury entails migration of myofibroblasts and smooth muscle cells from the adventitia and media into the intima, leading to subsequent aggressive neointimal hyperplasia (7). Numerous regulators mediate or modulate this biologic response, including cell cycle regulators, cytokines, chemokines, vasoactive molecules, adhesion molecules, and metallic matrix proteinases. For example, heme oxygenase-1 (HO-1) has antiproliferative properties. HO-1 knockout mice exhibit accelerated neointimal hyperplasia of their AVF, highlighting the physiologic role of HO-1 in attenuating neointimal hyperplasia (13). The clinical relevance of these experimental findings was demonstrated by
Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama Correspondence: Dr. Michael Allon, Division of Nephrology, University of Alabama at Birmingham, PB, Room 226, 1530 Third Avenue South, Birmingham, AL 35294. Email: [email protected]
Copyright © 2013 by the American Society of Nephrology
2183
2184
Clinical Journal of the American Society of Nephrology
Figure 1. | Pathogenesis of arteriovenous fistula (AVF) nonmaturation.
an observational study from Taiwan, which evaluated the association of AVF survival with HO-1 length polymorphisms in hemodialysis patients (19). A promoter gene regulates the transcription of HO-1. G-T length polymorphisms of this promoter affect HO-1 expression. The L/L genotype (longer GT repeats) is associated with a lower rate of HO-1 transcription than the S/S genotype (shorter GT repeats). Compared with the patients with the S/S genotype, those with the L/L genotype have shorter AVF patency. More recent research has focused on preexisting vascular pathology in hemodialysis patients, and its potential contribution to the pathogenesis of neointimal hyperplasia in new AVFs. Several arterial and venous abnormalities have been described in patients undergoing vascular access creation, including venous intimal hyperplasia, arterial intimal hyperplasia, arterial medial fibrosis, arterial calcification, and venous calcification (18,20–23). A plausible hypothesis is that preexisting vascular pathology predisposes to accelerated neointimal hyperplasia and juxtaanastomotic stenosis in patients receiving a new AVF. A pilot Korean study reported significantly decreased AVF patency in patients with preexisting arterial intimal hyperplasia compared with that observed in patients without this pathology (23). A second study found no association of preexisting arterial medial fibrosis or arterial calcification with AVF nonmaturation (18). In contrast, a third study observed a lower frequency of arteriovenous graft (AVG) interventions in patients with preexisting arterial or venous pathology, suggesting a protective effect against neointimal hyperplasia in vascular access (24). These contradictory findings suggest that the cellular mechanisms leading to neointimal hyperplasia after AVF creation differ from those leading to the preexisting ;vascular abnormalities in uremic patients. Dr. Lee’s article provides a comprehensive overview of the mediators and modulators of neointimal hyperplasia, and the experimental evidence on how they affect AVF maturation. What are the potential pharmacologic interventions to prevent vascular access failure? The only drug that has been evaluated for prevention of AVF nonmaturation is clopidogrel (25). A multicenter randomized clinical trial allocated patients to receive either clopidogrel or placebo for 6 weeks after AVF surgery. The frequency of AVF thrombosis within 6 weeks was significantly lower in patients
receiving clopidogrel (12.2% versus 19.5%; P50.02), but AVF nonmaturation was similar in both groups (61.8% versus 59.5%; P50.40). Four randomized studies have evaluated pharmacologic interventions to prevent AVG failure (stenosis or thrombosis). Neither warfarin nor aspirin 1 clopidogrel prevented AVG thrombosis, but both drug regimens increased the risk of bleeding complications (26,27). Dipyridamole 1 aspirin produced a modest, but significant, prolongation of primary unassisted AVG survival (28). Finally, fish oil decreased the frequency of angioplasty and thrombosis in new AVG (29). Systemic administration requires achieving relatively high blood drug levels in order to ensure sufficient antiproliferative effects at the target site (arteriovenous anastomosis for AVF and venous-graft anastomosis for AVG). These high systemic levels may expose the patients to significant adverse effects. There has been considerable interest in devising local drug delivery systems that would achieve a high drug level at the target site, while minimizing the risk of systemic drug toxicity (30). Potential local drug delivery systems, such as topical administration, adventitial wraps, cell implants, and gene delivery systems, have been evaluated in animal models. A limited number of phase 1/2 clinical trials have tested such therapies in dialysis patients. These pilot studies have included allogeneic endothelial cell implants (31), sirolimus-eluting collagen membranes (32), and pancreatic elastase (33). These small studies demonstrated the feasibility and safety of a variety of local drug delivery systems. However, large multicenter randomized clinical trials will be required to evaluate the clinical efficacy of these interventions in preventing vascular access failure. Drs. Terry and Dember have written a comprehensive review of new pharmacologic therapies in the horizon that may improve vascular access outcomes. Acknowledgments This manuscript was supported by funding from a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant (R01-DK-085027) to Dr. Allon. Disclosures None. References 1. Allon M: Current management of vascular access. Clin J Am Soc Nephrol 2: 786–800, 2007 2. Beathard GA, Arnold P, Jackson J, Litchfield T; Physician Operators Forum of RMS Lifeline: Aggressive treatment of early fistula failure. Kidney Int 64: 1487–1494, 2003 3. Asif A, Lenz O, Merrill D, Cherla G, Cipleu CD, Ellis R, Francois B, Epstein DL, Pennell P: Percutaneous management of perianastomotic stenosis in arteriovenous fistulae: Results of a prospective study. Kidney Int 69: 1904–1909, 2006 4. Turmel-Rodrigues L, Mouton A, Birmele´ B, Billaux L, Ammar N, Gre´zard O, Hauss S, Pengloan J: Salvage of immature forearm fistulas for haemodialysis by interventional radiology. Nephrol Dial Transplant 16: 2365–2371, 2001 5. Chang CJ, Ko PJ, Hsu LA, Ko YS, Ko YL, Chen CF, Huang CC, Hsu TS, Lee YS, Pang JH: 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, 2004 6. Lee T, Ullah A, Allon M, Succop P, El-Khatib M, Munda R, RoyChaudhury P: Decreased cumulative access survival in
Clin J Am Soc Nephrol 8: 2183–2185, December, 2013
7. 8.
9.
10. 11.
12. 13.
14. 15.
16. 17. 18.
19.
20.
21.
22.
23.
arteriovenous fistulas requiring interventions to promote maturation. Clin J Am Soc Nephrol 6: 575–581, 2011 Roy-Chaudhury P, Sukhatme VP, Cheung AK: Hemodialysis vascular access dysfunction: A cellular and molecular viewpoint. J Am Soc Nephrol 17: 1112–1127, 2006 Ene-Iordache B, Remuzzi A: Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: Low and oscillating shear stress locates the sites of stenosis. Nephrol Dial Transplant 27: 358–368, 2012 Ene-Iordache B, Cattaneo L, Dubini G, Remuzzi A: Effect of anastomosis angle on the localization of disturbed flow in ‘sideto-end’ fistulae for haemodialysis access. Nephrol Dial Transplant 28: 997–1005, 2013 Bharat A, Jaenicke M, Shenoy S: A novel technique of vascular anastomosis to prevent juxta-anastomotic stenosis following arteriovenous fistula creation. J Vasc Surg 55: 274–280, 2012 Manson RJ, Ebner A, Gallo S, Chemla E, Mantell MP, Deaton D, Roy-Chaudhury P: Arteriovenous fistula creation using the Optiflow vascular anastomosis device: A first in man pilot study. Semin Dial 26: 97–99, 2013 Peterson WJ, Barker J, Allon M: Disparities in fistula maturation persist despite preoperative vascular mapping. Clin J Am Soc Nephrol 3: 437–441, 2008 Juncos JP, Tracz MJ, Croatt AJ, Grande JP, Ackerman AW, Katusic ZS, Nath KA: Genetic deficiency of heme oxygenase-1 impairs functionality and form of an arteriovenous fistula in the mouse. Kidney Int 74: 47–51, 2008 Juncos JP, Grande JP, Kang L, Ackerman AW, Croatt AJ, Katusic ZS, Nath KA: MCP-1 contributes to arteriovenous fistula failure. J Am Soc Nephrol 22: 43–48, 2011 Langer S, Kokozidou M, Heiss C, Kranz J, Kessler T, Paulus N, Kru¨ger T, Jacobs MJ, Lente C, Koeppel TA: Chronic kidney disease aggravates arteriovenous fistula damage in rats. Kidney Int 78: 1312–1321, 2010 Castier Y, Lehoux S, Hu Y, Foteinos G, Tedgui A, Xu Q: Characterization of neointima lesions associated with arteriovenous fistulas in a mouse model. Kidney Int 70: 315–320, 2006 Roy-Chaudhury P, Arend L, Zhang J, Krishnamoorthy MS, Wang Y, Banerjee R, Samaha A, Munda R: Neointimal hyperplasia in early arteriovenous fistula failure. Am J Kidney Dis 50: 782–790, 2007 Allon M, Litovsky S, Young CJ, Deierhoi MH, Goodman J, Hanaway M, Lockhart ME, Robbin ML: Medial fibrosis, vascular calcification, intimal hyperplasia, and arteriovenous fistula maturation. Am J Kidney Dis 58: 437–443, 2011 Lin CC, Yang WC, Lin SJ, Chen TW, Lee WS, Chang CF, Lee PC, Lee SD, Su TS, Fann CS, Chung MY: Length polymorphism in heme oxygenase-1 is associated with arteriovenous fistula patency in hemodialysis patients. Kidney Int 69: 165–172, 2006 Lee TC, Chauhan V, Krishnamoorthy M, Wang Y, Arend L, Mistry MJ, El-Khatib M, Banerjee R, Munda R, Roy-Chaudhury P: Severe venous neointimal hyperplasia prior to dialysis access surgery. Nephrol Dial Transplant 26: 2264–2270, 2011 Lee T, Safdar N, Mistry MJ, Wang Y, Chauhan V, Campos B, Munda R, Cornea V, Roy-Chaudhury P: Preexisting venous calcification prior to dialysis vascular access surgery. Semin Dial 25: 592–595, 2012 Wasse H, Rivera AA, Huang R, Martinson DE, Long Q, McKinnon W, Naqvi N, Husain A: Increased plasma chymase concentration and mast cell chymase expression in venous neointimal lesions of patients with CKD and ESRD. Semin Dial 24: 688–693, 2011 Kim YO, Song HC, Yoon SA, Yang CW, Kim NI, Choi YJ, Lee EJ, Kim WY, Chang YS, Bang BK: Preexisting intimal hyperplasia of radial artery is associated with early failure of radiocephalic
Novel Paradigms for Dialysis Vascular Access, Allon
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