Can Venous Stenosis Be Prevented?

Eugene C. Kovalik and Steve J. SchwabDepartment of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina

Currently, more than 200,000 people annually are keptalive by maintenance hemodialysis therapy. To providethis form of renal replacement therapy, a reliable meansof accessing the vasculature is required. Currently, ac-cess needs are met by three methods: the primary arte-riovenous fistula (AVF), polytetrafluoroethylene (PTFE)grafts, and tunneled cuffed catheters. Of these three ac-cess modalities, only the first two are appropriate forlong-term maintenance hemodialysis. Unfortunately,only the primary AVF has shown reliable long-term pa-tency. The Canadian Hemodialysis Morbidity studyshowed a 71% lower risk of failure of an AVF as com-pared to PTFE grafts (1). Despite such data, PTFE graftsrepresent the main access modality of up to 73% of in-cident hemodialysis patients, although regional varia-tions of 23%–85% exist (2).

The preponderance of PTFE grafts and their higherfailure rate has led, in part, to the spiraling cost of treat-ing end-stage renal disease patients. Up to 25% of allhospital stays and up to 50% of the first year hemodi-alysis costs may be attributed to vascular access care(3–5). Due to the failure rate of PTFE grafts, the DialysisOutcome Quality Initiative guidelines recently publishedby the National Kidney Foundation recommend that pri-mary AVFs be attempted in at least 50% of all newpatients, with the goal that such fistulas will be success-ful in at least 40% (6).

For patients who, for whatever reason, cannot have aprimary AVF, strategies must be undertaken to providemaximum graft survival. When grafts fail, the cause offailure is graft thrombosis. The underlying cause ofthrombosis usually is stenosis of the venous outflowtract. Although the majority of stenoses occur at the graftvein anastomosis (roughly 45%), up to 34% of lesionscan be found in the runoff vessels, particularly the centralvenous system (7). Intimal hyperplasia appears to be re-sponsible for the stenotic lesions (8). The hyperplasiastems from medial smooth-muscle replication and mi-gration to the intimal area of the vessels, followed byfurther proliferation and matrix deposition (9, 10). Thesequence may be the natural result of the body’s re-sponse to injury. Unfortunately, this response is mal-adaptive for the needs of the hemodialysis patient.

Currently, the strategies available to the nephrologistto combat the problem of intimal hyperplasia rely mainlyon detecting lesions early and intervening with eitherangioplasty or surgical revision prior to access failure.

Various detection techniques are available such as ve-nous pressure, recirculation, Doppler flow, and onlineaccess blood flow monitoring. Unfortunately these tech-niques do nothing to prevent the underlying physiologicproblem. In future, researchers in vascular access thera-pies must address the problem of intimal proliferationbefore it can occur. The various stages of the process(smooth-muscle migration, proliferation or extracellularmatrix production) serve as targets for therapy. Threeareas are of particular interest: pharmacologic preventionof stenosis, graft irradiation to prevent intimal hyperpla-sia and, finally, genetic therapy aimed at interruptingintimal proliferation.

Very little work has been done in the use of drugs toinhibit myointimal proliferation in arteriovenous (AV)grafts. Hakim and Himmelfarb (11) recently reviewedthe literature. In new PTFE grafts, dipyridamole has beenshown, in small studies, to decrease the rate of throm-bosis, whereas aspirin use tends to increase thromboticevents (12). These drugs have no significant effects onpreviously thrombosed grafts (12). In one small study,ticlodipine also seemed to decrease thrombotic events inAV grafts (13). Fish oil has been used with mixed results(14). These agents are proposed to inhibit venous steno-ses by inhibiting both neointimal and fibromuscular hy-perplasia in the vein wall by direct action on vessel wallinjury, such action being mediated by cytokine-drivenpathways. The current proposal is that platelet-derivedgrowth factor (PDGF) and basic fibroblast growth factor(bFGF) may be the mediators of this vessel wall injury.Specific antagonists such as dipyridamole may slow orstop this response to injury. Proprietary experimentalagents with specific inhibitory action on these cytokinesare being actively investigated.

The paradoxical effect of aspirin as compared to di-pyridamole, according to Hakim and Himmelfarb (11), islikely due to its ability to inhibit both PDGF and bFGF.Aspirin results in an increase of PDGF-induced cell pro-liferation by inhibiting cyclooxygenase-derived inhibi-tion of smooth-muscle proliferation and stimulating li-poxygenase-mediated proliferation.

The use of irradiation to prevent restenosis after an-gioplasty with or without stent placement in the coronaryand peripheral arteries has been under investigation forseveral years. The technique applied involves the deliv-ery of beta-irradiation via an iridium wire to the angio-plasty site. The largest published human trial showedexcellent follow-up patency (15). Because the AV graftvein anastomosis accounts for nearly half of the lesionsfound in thrombosed grafts, this site is amenable to ra-diotherapy. In an abstract out of Emory University, in-ternal irradiation of the anastomosis after angioplastyyielded encouraging results (16), even though if ad-

Address correspondence to: Steve J. Schwab, MD, Divisionof Nephrology, Box 3014, Duke University Medical Center,Durham, NC 27710.Seminars in Dialysis—Vol 12, No 3 (May–June) 1999 pp.144–145

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dressed the problem after the stenosis occurred. Earlieranastomotic irradiation, perhaps at the time of initialgraft placement, may inhibit future development of inti-mal proliferation and the resultant stenosis.

One alternate approach is the amelioration of the veinwall injury in AV grafts, which is caused by turbulence,shear stress, or compliance mismatch. The use of a flareor an insert at the vein-graft anastomosis as part of theAV graft procedure may minimize the extent of suchinjury. Several new graft designs are being actively in-vestigated in clinical trials.

An exciting possibility for preventing intimal prolif-eration is the use of vectored gene therapy via viral ornonviral approaches. An excellent review by Sukhatme(17) summarizes the potential targets and modalities ofdelivery for gene therapy (Table 1).

In summary, great strides have been made in under-standing the pathophysiology of AV graft stenosis. Muchof the progress is attributable in part to advances in coro-

nary artery and bypass graft biology. During the 1980sand 1990s, techniques for detecting venous graft stenosisprior to thrombosis were developed. The use of angio-plasty technology and surgery helped to prolong graftsurvival. It is hoped that the next century will usher in anera when prevention of stenosis can occur at the time ofinitial graft placement. The first steps already are underway with the focus on increasing the number of primaryAVFs in our patient population and the development ofthe Dialysis Outcome Quality Initiative guidelines tohelp standardize the placement and care of hemodialysisvascular access.

References1. Churchill D, Taylor D, Cook R, et al.: Canadian Hemodialysis Morbidity

Study.Am J Kidney Dis19:214–234, 19922. Hirth R, Turenne M, Woods J, et al.: Predictors of type of vascular access in

hemodialysis patients.JAMA 276:1303–1308, 19963. Feldman HI, Kobrin S, Wasserstein A: Hemodialysis vascular access mor-

bidity. J Am Soc Nephrol7:523–535, 19964. Feldman H, Held P, Hutchinson J, et al.: Hemodialysis vascular access mor-

bidity in the United States.Kidney Int43:1091–1096, 19935. US Renal Data System:USRDS 1997 Annual Report. Washington, DC, 1997,

pp 143–1616. National Kidney Foundation–Dialysis Outcome Quality Initiative:Clinical

Practice Guidelines for Vascular Access.New York, National Kidney Foun-dation, 1997

7. Sullivan KL, Besarab A, Bonn J, et al.: Hemodynamics of failing dialysisgrafts.Radiology186:867–872, 1993

8. Sewdberg S, Brown B, Sigley R, et al.: Intimal fibromuscular hyperplasia atthe venous anastomosis of PTFE grafts in hemodialysis patients. Clinical,immunocytochemical, light and electron microscopic assessment.Circula-tion 80:1726–1736, 1989

9. Sottiurai V, Yao J, Flinn W, Batson R: Intimal hyperplasia and neointima:An ultrastructural analysis of thrombosed grafts in humans.Surgery93:809–817, 1983

10. Ross R. Atherosclerosis: A defense mechanism gone awry.Am J Pathol143:987–1002, 1993

11. Hakim R, Himmelfarb J: Hemodialysis access failure: A call to action.Kid-ney Int54:1029–1040, 1998

12. Sreedhara R, Himmelfarb J, Lazarus J, Hakim R: Antiplatelet therapy in graftthrombosis: Results of a prospective randomized double blinded study.Kid-ney Int45:1477–1483, 1994

13. Kobayashi K, Maeda K, Koshikawa S, et al.: Antithrombotic therapy withticlodipine in chronic renal failure patients on maintenance hemodialysis—amulticenter collaborative double blind study.Thromb Res20:255–261, 1980

14. Diskin C, Lock S, Tanja J: Intradialytic fish oil to decrease intimal hyper-plasia (abstract), inProceedings of the Twenty-Sixth Congress of the Euro-pean Dialysis Transplant Association, 1989, p 16

15. Tierstein P, Massullo V, Jani S, et al.: Catheter-based radiotherapy to inhibitrestenosis after coronary stenting.N Engl J Med336:1697–1703, 1997

16. Waksman R, Crocker I, Kikeri D, et al.: Endovascular low-dose radiation forprevention of restenosis following angioplasty for treatment of narroweddialysis ateriovenous grafts, inProceedings of the First Annual Conferenceon Interventional Endovascular Brachytherapy,New York, NY, May 30,1996

17. Sukhatme V: Vascular access stenosis: Prospects for prevention and therapy.Kidney Int49:1161–1174, 1996

TABLE 1. Gene therapy for venous stenosis

Target molecules and their actionsVascular cell adhesion molecule (VCAM): cell adhesionNitric oxide synthase (NOS): vasodilationPlatelet-derived growth factor (PDGF): migration, differentiationBasic fibroblast growth factor (bFGF): proliferation, angiogenesisTransforming growth factor–beta (TGF-b): fibrosis“Cell cycle” genes, (e.g., Rb, HSV-TK,myc): proliferationVascular epidermal growth factor (VEGF): angiogenesis

ApproachesDominant negative receptor constructs (soluble, transmembrane)Chimeric toxinsAntisense oligos

Target cellsEndothelial cells (ECs)Vascular smooth-muscle cells (VSMCs)

CaveatsFocus on wrong pathwaysDiversity of factors, redundancy

DeliveryLocation of lesion circumscribedLesion accessibleBlood flow interruptable for short periodsVein a thin vessel; application from inside or outsideVein normal at time of arteriovenous graft placementCell type that must be transduced (EC versus VSMC) depends

on gene to be deliveredExpression: long duration likely requiredSafety: chronic, nonlethal disease

Source:From V. Sukhatme, Vascular access stenosis: Prospects forprevention and therapy.Kidney Int49:1161–1174, 1996.

145CAN VENOUS STENOSIS BE PREVENTED?