**5. Translating science to therapies in hemodialysis vascular access dysfunction: from the bench to bedside**

There are currently few if any effective therapies to treat hemodialysis vascular access stenosis and neointimal hyperplasia. However, the knowledge obtained in recent years regarding the pathology and pathogenesis of vascular access access dysfunction has provided a framework for development of therapies that target neointimal hyperplasia and vascular stenosis. The purpose of the next section is to (1) describe current therapies for AVF and AVG stenosis and (2) novel therapies using localized delivery systems for AVF and AVG.

### **5.1 Systemic therapies**

Systemic therapies, such as dipyridamole, angiotensin-converting enzyme inhibitors, aspirin, and fish oil, from small clinical trials and observational studies have been shown to have the potential to block smooth muscle cell proliferation and migration and to prevent thrombosis in AVFs and AVGs 166-170. Most recently, two large randomized controlled trials, sponsored by the National Institutes of Health, evaluating anti-platelet agents in AVG and AVF to prevent neointimal hyperplasia were published 16,171. In the AVG study, dipyridamole and aspirin, modestly reduced the risk of stenosis and improved primary unassisted patency 171. In the AVF study clopidogrel reduced frequency of early thrombosis but did not improve AVF suitability defined as cannulation with two needles, minimum dialysis blood flow of 300ml/min, successful use 8/12 dialysis sessions, and use after 120 days from creation 16. While these two studies have shown some promising results, the clinical significance of these drugs used as standard treatment for hemodialysis access stenosis remains questionable.

Fish oil has been shown to prevent AVG stenosis and thrombosis in one randomized, controlled trial 172. Currently, another study evaluating fish oil and AVG stenosis and thrombosis is ongoing 173. Other systemic agents, though not tested in randomized clinical trials, which have shown potential anti-proliferative effects targeting neointimal hyperplasia in CVD or PVD models, include peroxisome proliferation-activated receptor agonist 174-176, sirolimus 177, and imatinib mesylate 176,178,179.

### **5.2 Radiation therapy**

372 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

sensitivity patterns that are grown at the dialysis center. Due to the high prevalence of methicillin-resistant *Staph Aureus* (MRSA), empiric therapy should include coverage for MRSA. When the specific organism and antibiotic sensitivities are identified, it is important to narrow the antibiotic therapy to prevent the development of drug resistant organisms. While the exact duration of antibiotic treatment for catheter-related bacteremia is uncertain, the Infectious Disease society of America recommends a 2 week course of antibiotics 153, while the K/DOQI guidelines recommends a 3 week course of antibiotics 19. Other therapies, which have been used in conjunction with systemic antibiotics, to treat catheterrelated bacteremia are antibiotic catheter locks. A number of studies have shown that antibiotic locks (which may treat the biofilm layer) used in conjunction with systemic antibiotics, in tunneled dialysis catheters, have documented a 70% cure rate 30,145,154-156. Recent studies have evaluated pharmacologic therapies to prevent catheter-related bacteremia. Routine application of topical antibiotic ointments at the CVC exit such as mupirocin, povidine-iodine, and polysporin triple ointment has been associated with a 73- 93% reduction in the risk of catheter-related bacteremia 7,151,157-159. Prophylactic antibiotic catheter locks have also recently been evaluated. A marked reduction in catheter-related bacteremia has been reported, ranging from 51-99%, with use of a prophylactic antibiotic catheter locking solution 7,160-164. However, of concern, a recent study has shown emergence of gentamicin-resistant organisms after 6 months when using a gentamicin-heparin

The above strategies for treatment of catheter-related bacteremia apply to patients who are clinically stable. However, catheter removal, in addition to antibiotic therapy, should be the treatment of choice when patients: (1) are clinically unstable, (2) have persistent fever for 48 hours, (3) have evidence of tunnel infection, or (4) develop metastatic infectious

There are currently few if any effective therapies to treat hemodialysis vascular access stenosis and neointimal hyperplasia. However, the knowledge obtained in recent years regarding the pathology and pathogenesis of vascular access access dysfunction has provided a framework for development of therapies that target neointimal hyperplasia and vascular stenosis. The purpose of the next section is to (1) describe current therapies for AVF and AVG stenosis and (2) novel therapies using localized delivery systems for AVF and

Systemic therapies, such as dipyridamole, angiotensin-converting enzyme inhibitors, aspirin, and fish oil, from small clinical trials and observational studies have been shown to have the potential to block smooth muscle cell proliferation and migration and to prevent thrombosis in AVFs and AVGs 166-170. Most recently, two large randomized controlled trials, sponsored by the National Institutes of Health, evaluating anti-platelet agents in AVG and AVF to prevent neointimal hyperplasia were published 16,171. In the AVG study, dipyridamole and aspirin, modestly reduced the risk of stenosis and improved primary unassisted patency 171. In the AVF study clopidogrel reduced frequency of early thrombosis but did not improve AVF suitability defined as cannulation with two needles, minimum

**5. Translating science to therapies in hemodialysis vascular access** 

prophylactic catheter lock 165.

**dysfunction: from the bench to bedside** 

complications 7.

AVG.

**5.1 Systemic therapies** 

Radiation therapy has been hypothesized to be a potential therapy to treat vascular stenosis due to its antiproliferative effects and potential beneficial effects of vascular remodeling180- 183. In experimental models, both external beam and endovascular radiation therapy has proven effective to reduce neointimal hyperplasia in AVF and AVG 184,185. However, in clinical studies, a recent randomized-controlled trial of in AVGs 25 patients showed that 42% of the radiated AVGs achieved the target lesion primary patency end point at 6 months as compared to 0% of the control group (p = 0.015), but this did not translate into an improvement in secondary patency at either 6 or 12 months 186.

### **5.3 Far infrared therapy**

Infrared radiation is an invisible electromagnetic wave with a longer wavelength than that of visible light. In experimental models, far infrared therapy has been shown to improve skin blood flow and endothelial function in cardiovascular disease 187-189. The rationale for far infrared therapy to treat dialysis vascular access stenosis is that the dialysis vascular access in patients are located at a superficial site and improving access flow may improve vascular access performance. In the lone clinical study of far infrared in dialysis access in AVFs, patients who received far infrared therapy had improved access flows and longer unassisted patencies 190.

### **5.4 Local drug delivery systems for hemodialysis access**

The rationale behind local delivery of drugs treat hemodialysis vascular access stenosis is that (1) AVFs and AVGs could be the ideal clinical model for the use of perivascular therapies since these can be easily applied at the time of surgery, (2) perivascular therapies preferentially target the "active" adventitia, (3) studies have demonstrated that lipophilic molecules when placed over the adventitia rapidly diffuse through all the layers of the vessel wall, and (4) small amounts of otherwise toxic drugs can be safely delivered to the site of stenosis using the perivascular approach resulting in high local concentrations with minimal systemic toxicity 4. The subsequent section will discuss local therapies to treat hemodialysis vascular access stenosis from experimental models and clinical studies.

### **5.4.1 Drug eluting paclitaxel perivascular wraps**

Experimental studies have previously demonstrated the efficacy of paclitaxel eluting wraps in AVG stenosis likely due to anti-proliferative effects 191-193. In 2007, a large multi-center randomized-controlled study, evaluating the use of paclitaxel-eluting mesh wraps, Vascular

of bare metal stents after angioplasty compared to angioplasty 201 alone has been shown to improve primary patency 202,203. However, bare-metal stents have yielded poor results due to aggressive development of in-stent restenosis. In experimental models of dialysis access in AVGs, drug-eluting stents have shown to reduce neointimal hyperplasia and improve luminal stenosis compared to bare-metal stents 204. However, there are no clinical studies

Stent grafts (covered stents constructed from the same material of AVGs) have received recent attention as a therapy for prevention of restenosis due to its ability to prevent elastic recoil and inability of the neointimal cells to penetrate the covered barrier. A recently published multicenter, randomized controlled, clinical trial showed stent grafts (Bard Peripheral Vascular, Tempe, AZ), placed after angioplasty, to treat venous stenosis had better primary unassisted patency compared to angioplasty alone 205. This is the only treatment to date that has shown to be effective to treat vascular access stenosis in a large,

Hemodynamic sheer stresses play a significant role in development of neointimal hyperplasia 87,112,206,207. Therefore, altering the sheer stress pattern to prevent turbulent, lowflow, and low-sheer stresses could reduce the development of neointimal hyperplasia. Previous clinical data to date to support such an intervention comes from several studies evaluating cuffed AVG grafts ("Venaflo"; Bard Vascular, Tempe Arizona) 208-210. In a recent randomized control trial evaluating cuffed vs non-cuffed AVG, cuffed AVGs showed better primary patency and cumulative survival 211. Finally, results from a newly developed anastomotic implant device, "OptiflowTM" (Bioconnect Systems; Ambler, PA), to connect the artery and vein in AVFs and improve hemodynamics by providing a symmetric flow pattern, have shown a primary patency of 83% at 90 days 212. This primary patency rate was

In the last decade our knowledge of vascular access dysfunction has significantly evolved. We now understand that the most common pathologic lesion seen in AVF and AVG dysfunction is aggressive venous neointimal hyperplasia, and biofilms and fibrin sheaths play a major role in CVC infection and dysfunction. In order to advance the field further, we need to further our current understanding of both the clinical and experimental pathways that result in venous neointimal hyperplasia and mechanisms that lead to biofilm and fibrin sheath production in CVCs by using the advanced technologies and tools in cellular and molecular biology, bioengineering, genomics, proteomics, and vascular imaging (ultrasound, computed tomography, and magnetic resonance imaging) 65,124,214. Finally, small and large animal models of AVF and AVG, which a number of investigators in this field have already developed 61,93,207,215-217, will play an essential role in "translating" our knowledge of pathophysiologic

The magnitude and costs of dialysis access dysfunction is clearly evident, and will only become magnified in the coming years as the prevalent dialysis population continues to

evaluating drug-eluting stents in dialysis access to date.

higher compared to other similarly published studies 213.

**6. Future perspectives: new frontiers in research** 

mechanisms in vascular access dysfunction to novel therapies for patients.

randomized, clinical trial.

**7. Conclusion** 

**5.6 Improving hemodynamics** 

WrapTM, (Angiotech Pharmaceuticals, Inc.; Vancouver, British Columbia, Canada), was initiated to study the effectiveness and safety of this therapy on primary AVG patency compared to a standard AVG. However, this study was recently suspended in 2009 following a data safety monitoring review, due to an imbalance in the incidence of infections in one of the arms (either control or treatment). An alternative approach is the use of sirolimus eluting COLL-R® wraps (Covalon Technologies Ltd: Mississauga, Ontario, Canada). An initial Phase II study demonstrated primary unassisted AVG patency of 75% and 38% at 1 and 2 years respectively with these wraps 194.
