CJASN ePress. Published on April 16, 2015 as doi: 10.2215/CJN.00190115

Attending Rounds

A Patient with Recurrent Arteriovenous Graft Thrombosis Michael Allon

Abstract Arteriovenous grafts (AVGs) are prone to frequent thrombosis that is superimposed on underlying hemodynamically significant stenosis, most commonly at the graft-vein anastomosis. There has been great interest in detecting AVG stenosis in a timely fashion and performing preemptive angioplasty, in the belief that this will prevent AVG thrombosis. Three surveillance methods (static dialysis venous pressure, flow monitoring, and duplex ultrasound) can detect AVG stenosis. Whereas observational studies have reported that surveillance with preemptive angioplasty substantially reduces AVG thrombosis, randomized clinical trials have failed to confirm such a benefit. There is a high frequency of early AVG restenosis after angioplasty caused by aggressive neointimal hyperplasia resulting from vascular injury. Stent grafts prevent AVG restenosis better than balloon angioplasty, but they do not prevent AVG thrombosis. Several pharmacologic interventions to prevent AVG failure have been evaluated in randomized clinical trials. Anticoagulation or aspirin plus clopidogrel do not prevent AVG thrombosis, but increase hemorrhagic events. Treatment of hyperhomocysteinemia does not prevent AVG thrombosis. Dipyridamole plus aspirin modestly decreases AVG stenosis or thrombosis. Fish oil substantially decreases the frequency of AVG stenosis and thrombosis. In patients who have exhausted all options for vascular access in the upper extremities, thigh AVGs are a superior option to tunneled internal jugular vein central vein catheters (CVCs). An immediate-use AVG is a reasonable option in patients with recurrent CVC dysfunction or infection. Tunneled femoral CVCs have much worse survival than internal jugular CVCs. Clin J Am Soc Nephrol ▪: ccc–ccc, 2015. doi: 10.2215/CJN.00190115

Patient Presentation The following vignette illustrates the numerous challenges in optimizing arteriovenous graft (AVG) patency in hemodialysis patients. A 28-year-old woman initiated peritoneal dialysis when she developed ESRD because of focal glomerular sclerosis. She was hospitalized with an intracerebral bleed caused by a ruptured aneurysm 1.5 years later. A ventricular-peritoneal shunt was placed to treat hydrocephalus, and she was anticoagulated with warfarin to keep the shunt patent. Because of residual left-sided weakness and inadequate family support, she was no longer able to perform peritoneal dialysis. A tunneled central vein catheter (CVC) was placed in the right internal jugular vein, and she was switched to maintenance hemodialysis. A left forearm arteriovenous fistula (AVF) clotted 2 weeks after its creation. A subsequent looped left upper-arm AVG was successfully cannulated 5 weeks after its creation. It clotted four times during the ensuing 6 months and was treated each time by an interventional radiologist or nephrologist, who performed percutaneous thrombectomy, in conjunction with angioplasty of a venous anastomotic stenosis. The patient resumed hemodialysis with an internal jugular CVC when the AVG failed. A right radiocephalic AVF required surgical revision to promote maturation and was cannulated successfully 7 months after its creation. When it failed 3.5 months later, a new CVC was placed. A subsequent right upper-arm graft failed after 6 months because of www.cjasn.org Vol ▪ ▪▪▪, 2015

Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama Correspondence: Dr. Michael Allon, Division of Nephrology, PB, Room 226, 1530 Third Avenue S, Birmingham, AL 35294. Email: [email protected]

irreversible thrombosis, despite undergoing two angioplasties and two thrombectomies. A new CVC was placed in the right femoral vein because an ultrasound had then revealed bilateral thrombosis of the central veins in her chest. Having exhausted vascular access options in both upper extremities during a 5-year period, she then had an immediate-use AVG (Gore) placed in her left thigh. This AVG required five thrombectomies, two angioplasties, and one surgical revision to maintain its patency for dialysis during the next 3 years. Therefore, over an 8.2-year period of hemodialysis, this patient required five new vascular access surgeries, 12 thrombectomies, four angioplasties, and two surgical revisions. She also underwent 15 CVC placements, exchanges, or removals and was treated for three episodes of catheter-related bacteremia. In summary, she averaged 4.4 vascular access procedures annually and was catheter-dependent for 1.8 years, or 22% of her time on hemodialysis. Unfortunately, she was disqualified for kidney transplant because of morbid obesity.

AVG Placement and Cannulation Surgeons create an AVG by interposing a hollow synthetic tube in a looped configuration, with one end anastomosed to the side of an artery and the other end to the side of a vein (Figure 1). The AVG is typically cannulated 2–3 weeks after its placement, once the Copyright © 2015 by the American Society of Nephrology

1

2

Clinical Journal of the American Society of Nephrology

surgical wound has healed. The initial cannulation is performed with 15-gauge needles inserted at a 45° angle with a dialysis blood flow of 450 ml/min.

Unfortunately, there is no reliable test to distinguish between an AVG with underlying stenosis that is destined to clot and one that will remain patent without an intervention.

Why Do AVGs Clot? Virchow’s triad (venous stasis, endothelial injury, and hypercoagulability) describes the three factors predisposing to venous thrombosis. The first two are the major contributors to AVG thrombosis. When patients undergo percutaneous thrombectomy of a clotted AVG, imaging studies almost always reveal an underlying hemodynamically significant (.50%) stenosis. The stenotic location is most commonly observed at the venous anastomosis, but it may also be found in the draining vein, central vein, feeding artery, or within the AVG itself (1–3). Successful restoration of AVG patency requires both mechanical thrombectomy and successful angioplasty of the underlying stenosis. These observations suggest that AVG thrombosis is a direct consequence of critical stenosis. This assumption is clearly an oversimplification, however, because only a fraction of AVG with hemodynamically significant stenosis will clot in the absence of a preemptive angioplasty. For example, in one prospective study of patients with .50% AVG stenosis documented by angiogram, only 30% of AVGs clotted during the ensuing 6 months without preemptive angioplasty (4). In other words, stenosis is necessary, but not sufficient, to cause AVG thrombosis.

Figure 1. | Schematic of a looped forearm arteriovenous graft. One end of the graft is anastomosed to the side of the brachial artery, and the other end is anastomosed to a vein in the antecubital fossa. Arteriovenous graft stenosis develops most commonly at the graft-vein anastomosis.

Can One Identify AVGs with Significant Stenosis by Noninvasive Methods? An angiogram is the definitive test to identify AVG stenosis, but it is invasive and expensive. Therefore, it is desirable to have a simple, reproducible, noninvasive test to identify patients who are likely to have AVG stenosis. Patients with an abnormal test would then be referred for an angiogram, and if it reveals hemodynamically significant stenosis, a preemptive angioplasty would be performed. The noninvasive tests for stenosis fall into two broad categories. Clinical monitoring consists of tests that can be performed in the dialysis unit without requiring special equipment or extensive staff training. AVG monitoring includes physical examination of the AVG (abnormal bruit, edema distal to the AVG); observations during the hemodialysis session (difficulty in cannulation, prolonged bleeding from the needle puncture site); and unexplained decrease in the delivered Kt/V on a constant dialysis prescription (3,5). Monitoring is simple and cheap, but it is dependent on having the dialysis staff implement it consistently. AVG surveillance is a method that requires either specialized equipment or extensive staff training. There are three major types of AVG surveillance. Static dialysis venous pressure measures the intragraft pressure before initiation of the dialysis session (6). The ratio of intragraft to systemic systolic pressure is normally ,0.4. A ratio .0.6 is suspicious for AVG stenosis. Flow monitoring measures the access blood flow using ultrasound dilution (7). With the arterial and venous lines reversed, ice saline is injected rapidly into the graft, and the rate of increase in blood temperature is used to calculate the blood flow. An access flow ,600 ml/min, or one that has decreased by .25% from the previous baseline, is considered suspicious for AVG stenosis. Finally, duplex ultrasound requires a visually apparent focus of narrowing, in conjunction with a ratio of the peak systolic velocity on either side of the stenosis being .2 (8). Static dialysis venous pressures and flow monitoring are typically performed by a trained individual at monthly intervals, and duplex ultrasound is usually done quarterly. A number of studies have evaluated the positive predictive value of an abnormality of clinical AVG monitoring or surveillance for the presence of hemodynamically significant stenosis. The values were 69%–93% for clinical monitoring (80% for physical examination, 69% for unexplained decrease in Kt/V, and 66% for difficulties encountered during the dialysis session) (3,5,8–10), 92% for static dialysis venous pressure (6), 87%–100% for flow monitoring (11,12), and 80% for duplex ultrasound (5). Because static dialysis venous pressure and flow monitoring may vary between repeated measurements, the typical approach is to look for trends (e.g., progressive increase in the intragraft to systemic systolic pressure or progressive decreases in the access blood flow) before referring the patient for an angiogram. In practice, this typically requires 2–3 months of repeated measurements before the angiogram is obtained. When stenosis progresses rapidly, it is quite possible for the AVG to clot before surveillance has identified a likely stenosis. In fact, approximately 25% of AVGs clot before an abnormal surveillance test has been obtained and confirmed (13,14).

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015

Does Stenosis Surveillance with Preemptive Angioplasty Prevent AVG Thrombosis? The rationale of AVG surveillance is to identify stenosis in a timely fashion and perform a preemptive angioplasty before the AVG clots. Such an approach makes sense intuitively. In fact, numerous observational studies have reported that implementation of routine AVG stenosis surveillance, in conjunction with preemptive angioplasty, markedly lowers the frequency of AVG thrombosis in comparison with a historical period without AVG surveillance (6,9,10,15–17). More recently, six randomized clinical trials (RCTs) have evaluated this research question (4,5,12,18–20) (Figure 2). These studies used different surveillance methods (static dialysis venous pressure, flow monitoring, or duplex ultrasound), whereas the control group underwent clinical monitoring alone (21). As one would expect, the frequency of angioplasty was always higher in the surveillance group than in the control arm. Thrombosis-free AVG survival was the primary end point in five of the studies, and none found a significant difference in this outcome between the surveillance arm and controls. In addition, five of the studies evaluated cumulative AVG survival (time to permanent failure), and only one demonstrated superior AVG survival in the

Recurrent Dialysis Graft Thrombosis, Allon

3

surveillance group. Finally, a meta-analysis of these RCTs concluded that AVG surveillance with preemptive angioplasty does not prevent AVG thrombosis (22).

Why Surveillance with Preemptive Angioplasty Does Not Prevent AVG Thrombosis AVG stenosis is caused by aggressive neointimal hyperplasia (23). The vascular injury caused by balloon angioplasty induces accelerated intimal hyperplasia, resulting in rapid restenosis (24). As a consequence, stenosis recurs in approximately 20% of AVGs within 1 week of angioplasty and in 40% within 1 month (11,12). In other words, the very intervention used to treat the underlying stenosis to prevent AVG thrombosis leads to rapidly recurrent stenosis that places the patient at risk for AVG thrombosis. As previously mentioned, we do not know which AVGs with hemodynamically significant stenosis are likely to clot and which ones will remain patent without a preemptive angioplasty. Therefore, the current sledgehammer approach results in elective angioplasty in all AVGs. Angioplasty may prevent AVG thrombosis in some AVGs that are destined to clot, but at the same time provoke thrombosis in other AVGs with stable stenosis. The net effect

Figure 2. | Effect of AVG stenosis surveillance with preemptive angioplasty on AVG thrombosis: Observational versus randomized studies. (A) Observational studies reporting on the frequency of graft thrombosis that occurred during a historical control period and after implementation of stenosis monitoring or surveillance. Thrombosis decreased during the intervention period in all of the studies. (B) The frequency of graft thrombosis in the graft surveillance group and the control group that was observed in randomized clinical trials. The rate of thrombosis was not significantly different between the randomized groups in these studies. AVG, arteriovenous graft; CM, clinical monitoring; DVP, dialysis venous pressure; FM, flow monitoring; SVP, static dialysis venous pressure; US, ultrasound. Reprinted from reference 21, with permission.

4

Clinical Journal of the American Society of Nephrology

is no change in the overall frequency of AVG thrombosis despite a large increase in angioplasty procedures (i.e., added cost without benefit).

Can Stent Deployment Improve AVG Outcomes after Angioplasty? One potential approach to improve AVG patency after angioplasty is to deploy a stent at the stenotic site. By providing a rigid scaffold inside the vessel, this may delay AVG restenosis. The efficacy of this approach was evaluated in an RCT in which patients with hemodynamically significant stenosis at the AVG venous anastomosis were allocated to receive either conventional angioplasty or angioplasty in conjunction with deployment of a stent graft (25). All patients underwent protocol angiograms 2 and 6 months after the initial intervention. The patients in the stent group had superior 6-month patency of the stenotic site and the entire access circuit. Importantly, the study design likely led to many superfluous angioplasties when there was no clinical indication to perform an angiogram. Moreover, the frequency of AVG thrombosis did not differ between the two groups. Given the high expense of stent grafts (approximately $2000 each) and their unproven benefit in terms of preventing AVG thrombosis, their routine deployment to treat AVG stenosis cannot be justified at this time (26). Two larger ongoing RCTs, RENOVA (flair endovascular stent graft post-approval trial) and REVISE (Gore Viabahn endoprosthesis versus percutaneous transluminal angioplasty to revise arteriovenous grafts at the venous anastomosis in hemodialysis patients) are evaluating two different brands of stent grafts to assess whether they improve AVG patency after angioplasty of a venous anastomotic stenosis. Once the results of these RCTs are available, it will be possible to reappraise the indications for stent deployment in patients with AVG stenosis.

Potential Pharmacologic Interventions to Prevent AVG Thrombosis or Failure There has been great interest in identifying pharmacologic approaches to prevent AVG stenosis and thrombosis. The published studies to date have evaluated the efficacy of warfarin, high-dose folic acid, antiplatelet agents, and fish oil (Table 1). Anticoagulation In a Canadian double-blinded RCT, warfarin failed to prevent AVG thrombosis, it but produced a major bleed in approximately 10% of the patients (27). The futility of warfarin is highlighted in the present patient, who experienced recurrent AVG thrombosis despite long-term anticoagulation while maintaining a therapeutic international normalized ratio. It is sometimes argued that anticoagulation may still be useful in the subset of patients who experience frequent AVG thrombosis because such patients may differ from those with less-frequent AVG thrombosis. For example, a retrospective, case-control study of 419 hemodialysis patients with and without vascular access thrombosis identified a genetic or acquired thrombophilia (e.g., factor V Leiden, lupus anticoagulant, prothrombin gene mutation, hyperhomocysteinemia, anticardiolipin antibody) in a higher proportion of patients with access thrombosis compared with those without access thrombosis (55% versus 39%) (28). Nonetheless, simply demonstrating an association

between thrombophilia and access thrombosis does not establish that the thrombophilic disorder is responsible for AVG thrombosis or that anticoagulation would prevent AVG thrombosis. Answering this question would require an RCT of anticoagulation in hemodialysis patients with thrombophilia who receive a new AVG. Until such a study has been performed, anticoagulation of such patients cannot be justified. Rather, the focus should be on pharmacologic approaches to prevent neointimal hyperplasia and stenosis (the underlying pathology leading to AVG thrombosis). Antiplatelet Agents Dipyridamole, an antiplatelet agent, also inhibits the proliferation of vascular smooth muscle cells in vitro, suggesting that it may prevent neointimal hyperplasia, stenosis, and thrombosis in AVGs (29). In a single-center, double-blinded RCT, dipyridamole decreased AVG thrombosis by approximately 50% (30). A much larger, multicenter, double-blinded RCT observed that aspirin plus long-acting dipyridamole improved primary unassisted AVG survival by approximately 18% (31). In another RCT, aspirin plus clopidogrel did not prevent AVG thrombosis thrombosis-free AVG, but doubled the frequency of bleeding complications (32). Therapy to Treat Hyperhomocysteinemia Homocysteine levels are extremely high in hemodialysis patients, and vascular access thrombosis has been associated with homocysteine levels (33), suggesting that decreasing plasma homocysteine may prevent vascular access thrombosis. Two RCTs evaluated this question by administering high doses of vitamin B. In one study a high (15 mg) daily dose of folic acid lowered plasma homocysteine levels without preventing access thrombosis (34). Likewise, a second RCT that used high doses of folic acid, pyridoxine, and cyanocobalamin to lower plasma homocysteine did not observe a reduction in AVG thrombosis (35). These two RCTs highlight an important principle: just because a therapy treats an underlying thrombophilia does not necessarily mean that it will prevent AVG thrombosis. Fish Oil The active component of fish oil, omega-3 fatty acids, has antiproliferative and antioxidant properties, which may help prevent AVG thrombosis (36). A small, single-center RCT demonstrated a markedly lower rate of AVG thrombosis in patients treated with fish oil versus placebo (37). A larger, multicenter, double-blinded RCT observed that fish oil halved the frequency of AVG thrombosis and angioplasty (38). Local Drug Delivery Systems There has been an ongoing interest during the last few years in developing local drug delivery systems that would provide a high concentration of an antiproliferative drug at the site of stenosis, while minimizing the potential toxicity associated with systemic administration of such drugs (39). Such an approach has been beneficial in a number of experimental animal models of AVGs (e.g., using a paclitaxel- or rapamycin-eluting wraps), but no large-scale RCTs in patients with AVGs have been completed.

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015

Recurrent Dialysis Graft Thrombosis, Allon

5

Table 1. Randomized clinical trials of pharmacologic interventions to improve arteriovenous graft outcomes

Intervention Anticoagulation (warfarin) Antiplatelet agents Aspirin plus clopidogrel Dipyridamole6 aspirin Dipyridamole plus aspirin Lowering homocysteine High-dose folic acid High-dose folic acid, pyridoxine, and vitamin B12 Fish oil

Primary Access End Point

Author (yr)

No. of pts

Results

Crowther, 2002 (27)

107

AVG thrombosis

No decrease in thrombosis; high frequency of major hemorrhage

Kaufman, 2003 (32)

200

Access thrombosis

Sreedhara, 1994 (30)

84

Access thrombosis

No difference, but more hemorrhage with active drug Approximately 50% decrease in thrombosis 18% decrease

Dixon, 2009 (31)

649

Loss of primary unassisted patency

Wrone, 2004 (34) Jamison, 2007 (35)

510 751

Access thrombosis Access thrombosis

No difference No difference

Schmitz, 2002 (37) Lok, 2012 (38)

24 201

Access thrombosis Loss of primary unassisted patency

Decrease in thrombosis Trend of fewer end points (P50.06); approximately 50% decrease in frequency of AVG thrombosis and angioplasty

pts, patients; AVG, arteriovenous graft.

Once All Upper-Extremity Options for Permanent Vascular Access Have Been Exhausted, What Is the Best Access Option? A subset of hemodialysis patients, such as the one described in the current patient presentation, experience multiple failed vascular accesses and ultimately exhaust all options for permanent vascular access in the upper extremities. Assuming that peritoneal dialysis is not a viable option, such patients may continue hemodialysis with a long-term tunneled CVC. Alternatively, the surgeon can create an AVG in the thigh. A recent observational study compared the longterm access outcomes in a large cohort of hemodialysis patients with tunneled internal jugular CVCs versus thigh AVGs (40). Infection-free survival at 1 year was 79% for thigh AVGs versus 21% for CVCs. Cumulative access survival at 1 year was 62% for thigh AVGs versus 31% for CVCs. Therefore, in this clinical scenario, thigh AVGs are a much superior option that is associated with fewer infections and more prolonged access survival. In patients with a patent artery but an occluded central vein, another access option is placement of a hemodialysis reliable outflow graft (41).

What Is the Role of an Immediate-Use AVG? Conventional polytetrafluoroethylene (PTFE) AVGs typically require 2–3 weeks before they can be safely cannulated. In contrast, immediate-use AVGs are made of polyurethane and include a special middle layer with a nonpermeable self-sealable coat that permits them to be safely cannulated within 24 hours of their placement (42). Under what circumstances is the use of immediate-use AVG justified? One scenario is the situation in which CVC

dysfunction recurs rapidly (within days) and repeatedly, such that it impairs adequate delivery of dialysis. A second scenario is a patient with frequent catheter-related bacteremia necessitating multiple courses of antibiotics, thereby delaying placement of the AVG (43). At one large dialysis center, immediate-use AVGs accounted for only 3.5% of all AVGs placed during a 5-year period (44). Compared with standard PTFE AVGs, the immediate-use AVGs have a similar cumulative patency. However, they had a higher frequency of AVG infection, particularly if they were placed in the thigh (44).

What Vascular Access Options Are Possible When All Permanent Access Options Have Been Exhausted and Central Thoracic Veins Are Occluded? Once a patient has exhausted all options for permanent vascular access options in all four extremities, that patient remains CVC-dependent unless peritoneal dialysis is feasible. Approximately 5% of hemodialysis patients fall into this category (45). Central vein stenosis and thrombosis are common complications of long-term CVCs (46). Once the patient develops bilateral occlusion of the central veins in the chest, central veins at other locations are used for vascular access. The most commonly used choice is the femoral artery. Unfortunately, femoral CVCs are short-lived and far inferior to those placed in the internal jugular vein. At one clinical center, the 6-month patency of CVCs (from initial placement to removal or exchange) was only 14% for femoral CVCs compared with 67% for internal jugular CVCs (47). Moreover, 26% of patients with femoral CVCs developed ipsilateral deep vein thrombosis requiring anticoagulation (47). Other less commonly used sites for CVCs

6

Clinical Journal of the American Society of Nephrology

include transhepatic CVCs and translumbar CVCs placed into the inferior vena cava (48,49). In summary, AVGs have relatively poor long-term patency and usually fail as a result of irreversible thrombosis superimposed on underlying stenosis. AVG surveillance can detect stenosis before thrombosis and can lead to timely pre-emptive angioplasty. However, surveillance with pre-emptive angioplasty did not prevent AVG thrombosis in RCTs. Several pharmacologic approaches to preventing AVG stenosis and thrombosis have been evaluated.

(57–60). In contrast, no clinical factors have been associated with early AVG failure. Therefore, for example, a recent prospective, multicenter study of 354 patients with new AVGs did not observe an association of early AVG failure with patient age, sex, race, diabetes, cardiovascular disease, body mass index, or access location (61).

Questions

Answer Heme-oxygenase-1 polymorphisms were associated with AVF failure in one report (62). Thrombophilia (genetic abnormalities associated with a hypercoagulable state, such as factor V Leiden, prothrombin mutation, or decreased activity of protein S or C) was present in 9% of 219 patients undergoing AVF creation and was associated with a 2.2-fold higher risk for AVF failure (63). Another prospective study of 479 patients with new AVFs investigated the association of AVF failure with 43 single-nucleotide polymorphisms (SNPs) in 26 candidate genes related to proliferation, inflammation, endothelial function, vascular remodeling, coagulation, and calcium/phosphate metabolism (64). Only two of the candidate SNPs studied (one for factor V and one for LDL receptor-related protein 1), accounting for 17% of the study cohort, were associated with AVF failure. Finally, a third study of 354 patients with new AVGs evaluated whether AVG failure was associated with 48 SNPs associated with nine candidate genes (61). Factor V polymorphisms, found in 47% of the patients, were associated with a 1.7-fold higher risk of AVG failure. Should patients with frequent AVG thrombosis be screened for such genetic abnormalities? Genetic screening is expensive, and it is not known whether anticoagulation of these individuals would prevent future AVG thrombosis. In the absence of an RCT, such an approach cannot be recommended.

Manish K. Saha, MD (Nephrology Fellow at University of Alabama at Birmingham) Has anybody looked at using drug-eluting stents, such as those used for coronary artery disease, to prevent AVG failure? Answer Sirolimus-eluting stents have been shown to reduce intimal hyperplasia in a porcine model of an AVG (50). To date, there have been no clinical studies evaluating this approach in hemodialysis patients with an AVG. In addition, an ongoing open-label, single-center, RCT of 40 hemodialysis patients revealed superior 6-month primary access patency in patients treated with a paclitaxel-coated angioplasty balloon compared with those treated with a standard angioplasty balloon (51). Larger clinical trials are indicated before this approach can be recommended. Vinay N. Krishna, MD (Nephrology Fellow at University of Alabama at Birmingham) Can preoperative venous mapping predict outcomes of AVF and AVG? Answer Preoperative vascular mapping assists surgeons in selecting the type and location of vascular access. It provides information about arterial and venous diameters and stenosis or thrombosis of the draining vein (52). Use of arteries or veins ,1.5 mm in diameter is associated with higher AVF nonmaturation (53), prompting most surgeons to require arterial diameters .2 mm and venous diameters $2.5 mm. However, using even higher vascular diameters does not lower AVF nonmaturation (54). The effect of preoperative vascular diameters on AVG survival has not been reported. However, access survival is comparable for AVGs placed in the thigh and in the upper extremity, even though the former use considerably larger vessels (55). The possibility that vascular function tests may be better predictors of AVF outcome is currently being investigated (56). James C. Harms, MD (Nephrology Fellow at University of Alabama at Birmingham) Are any patient characteristics associated with AVG stenosis or thrombosis? Answer AVF nonmaturation or early failure is associated with older age, female sex, forearm location, and cardiovascular disease

Claretha N. Lyas, MD (Nephrology Fellow at University of Alabama at Birmingham) Are there any genetic factors that predispose to early access failure?

Acknowledgments Supported by a National Institute of Diabetes and Digestive and Kidney Diseases grant (no. R01-DK085027) to Dr. Allon. Disclosures None. References 1. Beathard GA: Percutaneous transvenous angioplasty in the treatment of vascular access stenosis. Kidney Int 42: 1390–1397, 1992 2. Lilly RZ, Carlton D, Barker J, Saddekni S, Hamrick K, Oser R, Westfall AO, Allon M: Predictors of arteriovenous graft patency after radiologic intervention in hemodialysis patients. Am J Kidney Dis 37: 945–953, 2001 3. Maya ID, Oser R, Saddekni S, Barker J, Allon M: Vascular access stenosis: Comparison of arteriovenous grafts and fistulas. Am J Kidney Dis 44: 859–865, 2004 4. Lumsden AB, MacDonald MJ, Kikeri D, Cotsonis GA, Harker LA, Martin LG: Prophylactic balloon angioplasty fails to prolong the patency of expanded polytetrafluoroethylene arteriovenous grafts: Results of a prospective randomized study. J Vasc Surg 26: 382–390, discussion 390–392, 1997 5. Robbin ML, Oser RF, Lee JY, Heudebert GR, Mennemeyer ST, Allon M: Randomized comparison of ultrasound surveillance

Clin J Am Soc Nephrol ▪: ccc–ccc, ▪▪▪, 2015

6. 7. 8.

9.

10.

11.

12.

13. 14. 15. 16.

17. 18. 19. 20. 21. 22.

23.

24.

25.

26.

and clinical monitoring on arteriovenous graft outcomes. Kidney Int 69: 730–735, 2006 Besarab A, Sullivan KL, Ross RP, Moritz MJ: Utility of intra-access pressure monitoring in detecting and correcting venous outlet stenoses prior to thrombosis. Kidney Int 47: 1364–1373, 1995 Krivitski NM: Theory and validation of access flow measurement by dilution technique during hemodialysis. Kidney Int 48: 244– 250, 1995 Robbin ML, Oser RF, Allon M, Clements MW, Dockery J, Weber TM, Hamrick-Waller KM, Smith JK, Jones BC, Morgan DE, Saddekni S: Hemodialysis access graft stenosis: US detection. Radiology 208: 655–661, 1998 Cayco AV, Abu-Alfa AK, Mahnensmith RL, Perazella MA: Reduction in arteriovenous graft impairment: Results of a vascular access surveillance protocol. Am J Kidney Dis 32: 302–308, 1998 Safa AA, Valji K, Roberts AC, Ziegler TW, Hye RJ, Oglevie SB: Detection and treatment of dysfunctional hemodialysis access grafts: Effect of a surveillance program on graft patency and the incidence of thrombosis. Radiology 199: 653–657, 1996 Schwab SJ, Oliver MJ, Suhocki P, McCann R: Hemodialysis arteriovenous access: Detection of stenosis and response to treatment by vascular access blood flow. Kidney Int 59: 358–362, 2001 Moist LM, Churchill DN, House AA, Millward SF, Elliott JE, Kribs SW, DeYoung WJ, Blythe L, Stitt LW, Lindsay RM: Regular monitoring of access flow compared with monitoring of venous pressure fails to improve graft survival. J Am Soc Nephrol 14: 2645–2653, 2003 McDougal G, Agarwal R: Clinical performance characteristics of hemodialysis graft monitoring. Kidney Int 60: 762–766, 2001 Dember LM, Holmberg EF, Kaufman JS: Value of static venous pressure for predicting arteriovenous graft thrombosis. Kidney Int 61: 1899–1904, 2002 Schwab SJ, Raymond JR, Saeed M, Newman GE, Dennis PA, Bollinger RR: Prevention of hemodialysis fistula thrombosis. Early detection of venous stenoses. Kidney Int 36: 707–711, 1989 Allon M, Bailey R, Ballard R, Deierhoi MH, Hamrick K, Oser R, Rhynes VK, Robbin ML, Saddekni S, Zeigler ST: A multidisciplinary approach to hemodialysis access: Prospective evaluation. Kidney Int 53: 473–479, 1998 McCarley P, Wingard RL, Shyr Y, Pettus W, Hakim RM, Ikizler TA: Vascular access blood flow monitoring reduces access morbidity and costs. Kidney Int 60: 1164–1172, 2001 Ram SJ, Work J, Caldito GC, Eason JM, Pervez A, Paulson WD: A randomized controlled trial of blood flow and stenosis surveillance of hemodialysis grafts. Kidney Int 64: 272–280, 2003 Dember LM, Holmberg EF, Kaufman JS: Randomized controlled trial of prophylactic repair of hemodialysis arteriovenous graft stenosis. Kidney Int 66: 390–398, 2004 Malik J, Slavikova M, Svobodova J, Tuka V: Regular ultrasonographic screening significantly prolongs patency of PTFE grafts. Kidney Int 67: 1554–1558, 2005 Allon M: Do we really need periodic monitoring of vascular access for hemodialysis? NephSAP 6: 111–116, 2007 Tonelli M, James M, Wiebe N, Jindal K, Hemmelgarn B; Alberta Kidney Disease Network: Ultrasound monitoring to detect access stenosis in hemodialysis patients: A systematic review. Am J Kidney Dis 51: 630–640, 2008 Roy-Chaudhury P, Kelly BS, Miller MA, Reaves A, Armstrong J, Nanayakkara N, Heffelfinger SC: Venous neointimal hyperplasia in polytetrafluoroethylene dialysis grafts. Kidney Int 59: 2325– 2334, 2001 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 Haskal ZJ, Trerotola S, Dolmatch B, Schuman E, Altman S, Mietling S, Berman S, McLennan G, Trimmer C, Ross J, Vesely T: Stent graft versus balloon angioplasty for failing dialysis-access grafts. N Engl J Med 362: 494–503, 2010 Salman L, Asif A: Stent graft for nephrologists: Concerns and consensus. Clin J Am Soc Nephrol 5: 1347–1352, 2010

Recurrent Dialysis Graft Thrombosis, Allon

7

27. 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 28. Knoll GA, Wells PS, Young D, Perkins SL, Pilkey RM, Clinch JJ, Rodger MA: Thrombophilia and the risk for hemodialysis vascular access thrombosis. J Am Soc Nephrol 16: 1108–1114, 2005 29. Himmelfarb J, Couper L: Dipyridamole inhibits PDGF- and bFGF-induced vascular smooth muscle cell proliferation. Kidney Int 52: 1671–1677, 1997 30. Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM: Anti-platelet therapy in graft thrombosis: Results of a prospective, randomized, double-blind study. Kidney Int 45: 1477–1483, 1994 31. 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 32. 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 33. Shemin D, Lapane KL, Bausserman L, Kanaan E, Kahn S, Dworkin L, Bostom AG: Plasma total homocysteine and hemodialysis access thrombosis: A prospective study. J Am Soc Nephrol 10: 1095–1099, 1999 34. Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP: Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol 15: 420–426, 2004 35. Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD, Gaziano JM; Veterans Affairs Site Investigators: Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: A randomized controlled trial. JAMA 298: 1163–1170, 2007 36. Friedman A, Moe S: Review of the effects of omega-3 supplementation in dialysis patients. Clin J Am Soc Nephrol 1: 182– 192, 2006 37. Schmitz PG, McCloud LK, Reikes ST, Leonard CL, Gellens ME: Prophylaxis of hemodialysis graft thrombosis with fish oil: Double-blind, randomized, prospective trial. J Am Soc Nephrol 13: 184–190, 2002 38. Lok CE, Moist L, 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 39. Li L, Terry CM, Shiu YT, Cheung AK: Neointimal hyperplasia associated with synthetic hemodialysis grafts. Kidney Int 74: 1247–1261, 2008 40. Ong S, Barker-Finkel J, Allon M: Long-term outcomes of arteriovenous thigh grafts in hemodialysis patients: A comparison with tunneled dialysis catheters. Clin J Am Soc Nephrol 8: 804–809, 2013 41. Nassar GM, Glickman MH, McLafferty RB, Croston JK, Zarge JI, Katzman HE, Peden EK, Lawson JH, Martinez JM, Thackeray L: A comparison between the HeRO graft and conventional arteriovenous grafts in hemodialysis patients. Semin Dial 27: 310–318, 2014 42. Glickman MH, Stokes GK, Ross JR, Schuman ED, Sternbergh WC 3rd, Lindberg JS, Money SM, Lorber MI: Multicenter evaluation of a polytetrafluoroethylene vascular access graft as compared with the expanded polytetrafluoroethylene vascular access graft in hemodialysis applications. J Vasc Surg 34: 465–472, discussion 472–473, 2001 43. Chemla ES, Nelson S, Morsy M: Early cannulation grafts in straight axillo-axillary angioaccesses avoid central catheter insertions. Semin Dial 24: 456–459, 2011

8

Clinical Journal of the American Society of Nephrology

44. Maya ID, Weatherspoon J, Young CJ, Barker J, Allon M: Increased risk of infection associated with polyurethane dialysis grafts. Semin Dial 20: 616–620, 2007 45. Lee T, Barker J, Allon M: Tunneled catheters in hemodialysis patients: Reasons and subsequent outcomes. Am J Kidney Dis 46: 501–508, 2005 46. Wilkin TD, Kraus MA, Lane KA, Trerotola SO: Internal jugular vein thrombosis associated with hemodialysis catheters. Radiology 228: 697–700, 2003 47. Maya ID, Allon M: Outcomes of tunneled femoral hemodialysis catheters: Comparison with internal jugular vein catheters. Kidney Int 68: 2886–2889, 2005 48. Nadolski GJ, Trerotola SO, Stavropoulos SW, Shlansky-Goldberg RD, Soulen MC, Farrelly C: Translumbar hemodialysis catheters in patients with limited central venous access: Does patient size matter? J Vasc Interv Radiol 24: 997–1002, 2013 49. Smith TP, Ryan JM, Reddan DN: Transhepatic catheter access for hemodialysis. Radiology 232: 246–251, 2004 50. Rotmans JI, Pattynama PM, Verhagen HJ, Hino I, Velema E, Pasterkamp G, Stroes ES: Sirolimus-eluting stents to abolish intimal hyperplasia and improve flow in porcine arteriovenous grafts: A 4-week follow-up study. Circulation 111: 1537–1542, 2005 51. Katsanos K, Karnabatidis D, Kitrou P, Spiliopoulos S, Christeas N, Siablis D: Paclitaxel-coated balloon angioplasty vs. plain balloon dilation for the treatment of failing dialysis access: 6-month interim results from a prospective randomized controlled trial. J Endovasc Ther 19: 263–272, 2012 52. Robbin ML, Gallichio MH, Deierhoi MH, Young CJ, Weber TM, Allon M: US vascular mapping before hemodialysis access placement. Radiology 217: 83–88, 2000 53. Malovrh M: Non-invasive evaluation of vessels by duplex sonography prior to construction of arteriovenous fistulas for haemodialysis. Nephrol Dial Transplant 13: 125–129, 1998 54. Maya ID, O’Neal JC, Young CJ, Barker-Finkel J, Allon M: Outcomes of brachiocephalic fistulas, transposed brachiobasilic fistulas, and upper arm grafts. Clin J Am Soc Nephrol 4: 86–92, 2009

55. Miller CD, Robbin ML, Barker J, Allon M: Comparison of arteriovenous grafts in the thigh and upper extremities in hemodialysis patients. J Am Soc Nephrol 14: 2942–2947, 2003 56. Dember LM, Imrey PB, Beck GJ, Cheung AK, Himmelfarb J, Huber TS, Kusek JW, Roy-Chaudhury P, Vazquez MA, Alpers CE, Robbin ML, Vita JA, Greene T, Gassman JJ, Feldman HI; Hemodialysis Fistula Maturation Study Group: Objectives and design of the hemodialysis fistula maturation study. Am J Kidney Dis 63: 104–112, 2014 57. Allon M, Robbin ML: Increasing arteriovenous fistulas in hemodialysis patients: Problems and solutions. Kidney Int 62: 1109– 1124, 2002 58. Lok CE, Allon M, Moist LM, Oliver MJ, Shah H, Zimmerman D: Risk equation determining unsuccessful cannulation events and failure to maturation in arteriovenous fistulas (REDUCE FTM I). J Am Soc Nephrol 17: 3204–3212, 2006 59. Peterson WJ, Barker J, Allon M: Disparities in fistula maturation persist despite preoperative vascular mapping. Clin J Am Soc Nephrol 3: 437–441, 2008 60. Richardson AI 2nd, Leake A, Schmieder GC, Biuckians A, Stokes GK, Panneton JM, Glickman MH: Should fistulas really be first in the elderly patient? J Vasc Access 10: 199–202, 2009 61. Allon M, Zhang L, Maya ID, Bray MS, Fernandez JR; Dialysis Access Consortium (DAC) Study Investigators: Association of factor V gene polymorphism with arteriovenous graft failure. Am J Kidney Dis 59: 682–688, 2012 62. 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 63. Salmela B, Hartman J, Peltonen S, Alba¨ck A, Lassila R: Thrombophilia and arteriovenous fistula survival in ESRD. Clin J Am Soc Nephrol 8: 962–968, 2013 64. Verschuren JJ, Ocak G, Dekker FW, Rabelink TJ, Jukema JW, Rotmans JI: Candidate gene analysis of arteriovenous fistula failure in hemodialysis patients. Clin J Am Soc Nephrol 8: 1358– 1366, 2013 Published online ahead of print. Publication date available at www. cjasn.org.