**4.1 Catheter dysfunction**

Catheter dysfunction can occur immediately after placement or in a catheter which has been previously functioning without difficulties, and most commonly manifests with low catheter blood flows during dialysis or negative arterial pressures on the dialysis machine 6. In more severe cases catheter thrombosis is characterized by the inability to aspirate blood from the dialysis port 6. Catheter dysfunction which occurs immediately after placement is most likely due to placement problems 6.

Installation of a thrombolytic agent for 30 to 60 minutes is a treatment for catheter dysfunction, followed by a second installation if necessary 6. Recently published studies have reported varied success rate when treating catheter dysfunction with thrombolytics, ranging anywhere between 60-95% 26,28,35,127,128. When thrombolytic therapy is unsuccessful in providing adequate blood flow and adequate dialysis, despite repeated installations, then catheter exchange needs to be performed. The current K/DOQI guidelines recommends treatment with thrombolytic agents in all catheters with a persistently low blood flow rate (<300 ml/min) 19.

of recent studies in AVGs have supported the concept of a migration of adventitial cells into the intima where they contribute to final neointimal volume 59,112. In addition, recent data from several experimental AVF stenosis models have shown that smooth muscle cells in the neointima, may in part, originate from bone-marrow-derived cells that bind to the site of vascular injury and later differentiate into a smooth muscle cell phenotype in the neointima 82,113,114. From a therapeutic standpoint, it is likely that better information about the true source of neointimal cells will allow for the development of novel therapeutic interventions

**3.3 Hemodynamic and vascular remodeling in hemodialysis access dysfunction**  A number of experimental studies have shown that turbulent, low flow, low fluid sheer stress are involved in neointimal hyperplasia development 115-119. High sheer stress has been associated with vascular dilatation through inhibition of smooth muscle cell proliferation and high levels of nitric oxide release, whereas low sheer stress has been associated with smooth muscle cell proliferation and lack of vasodilatation 120-123. Poor hemodynamic profiles could be a risk factor for neointimal hyperplasia development and poor venous dilatation, and the degree of luminal stenosis is dependent upon both the magnitude of neointimal hyperplasia and the capacity for vasodilatation or vasocontriction. Therefore, a significant amount of neointimal hyperplasia and medial hypertrophy may not result in luminal stenosis in the presence of adequate vasodilatation, while a small amount of neointimal hyperplasia, but with poor vasodilatation, may result in severe venous stenosis 4,124. Unfortunately, the factors that are responsible for vascular remodeling are unknown, but adventitial angiogenesis and scar formation are hypothesized to play a significant role125,126. Thus, the ideal therapy for vascular stenosis would be an intervention that would

prevent vascular constriction (adverse remodeling) and neointimal hyperplasia4

a brief overview of catheter dysfunction and catheter-related infections.

CVC dysfunction and related-infection remains a common cause of morbidity, mortality, and high economic costs in treating chronic hemodialysis patients. This section will provide

Catheter dysfunction can occur immediately after placement or in a catheter which has been previously functioning without difficulties, and most commonly manifests with low catheter blood flows during dialysis or negative arterial pressures on the dialysis machine 6. In more severe cases catheter thrombosis is characterized by the inability to aspirate blood from the dialysis port 6. Catheter dysfunction which occurs immediately after placement is most

Installation of a thrombolytic agent for 30 to 60 minutes is a treatment for catheter dysfunction, followed by a second installation if necessary 6. Recently published studies have reported varied success rate when treating catheter dysfunction with thrombolytics, ranging anywhere between 60-95% 26,28,35,127,128. When thrombolytic therapy is unsuccessful in providing adequate blood flow and adequate dialysis, despite repeated installations, then catheter exchange needs to be performed. The current K/DOQI guidelines recommends treatment with thrombolytic agents in all catheters with a persistently low blood flow rate

targeting specific cell types.

**4. Central venous dialysis catheters** 

**4.1 Catheter dysfunction** 

(<300 ml/min) 19.

likely due to placement problems 6.

The current standard of care to prevent catheter thrombosis is installation of an anticoagulant in both dialysis ports at the completion of each dialysis session. In the United States, heparin is most commonly used, while in Europe citrate is the more common anticoagulant 6. The studies to-date have shown similar efficacy when comparing citrate to heparin for prophylaxis of catheter thrombosis, but with fewer complications of systemic bleeding with citrate 129-132. A recent multicenter, randomized-controlled trial has reported that use of a thrombolytic, tissue plasminogen activator as a locking solution compared to heparin had reduced incidence of catheter dysfunction 34.

### **4.2 Catheter-related bacteremia**

Currently, a precise definition for diagnosis catheter-related bacteremia is lacking. More rigorous definitions require a positive blood culture obtained from the catheter and a peripheral vein with the quantitative colony count being at minimum four-fold higher from the catheter sample 133. However, recently, the Infectious Disease Society of America has recognized the challenges in obtaining peripheral blood cultures from hemodialysis patients (e.g. priority for preserving veins and difficult cannulations) and has considered a definition of "possible" catheter-related bacteremia as positive blood culture obtained from the catheter in a symptomatic patient 134.

The two main pathways where organisms can gain entry into the blood stream to initiate catheter-related bacteremia are intraluminal and extraluminal 135. Organisms gain entrance through the bloodstream extraluminally through contact between the skin surface organisms and the external surface of the catheter at the time of catheter placement or following catheter placement before healing of the exit site or endothelialization of the subcutaneous tunnel 7. Subsequently, the organisms colonize or migrate through the intracutaneous exterior tract of the catheter to the tip, allowing for hematagenous dispersion of the organisms and leading to catheter-related bacteremia 7. Intraluminal-derived infections results from the transfer of organisms from hand contact with the catheter, leading to contamination of the internal catheter surfaces 7. Infection from the extraluminal pathway most commonly occurs immediately after catheter insertion, while infections from the intraluminal pathway occurs throughout the life of the catheter 7. Irrespective of the route of bacterial entry, the bacteria will either adhere to the CVC or become incorporated into a fibrin sheath. Adherence of the bacterial organisms to the CVC initiates a common pathway of biofilm production. A mature biofilm is a self-sustaining colony of microorganism, guarded by an exopolysaccharide matrix, that is stimulated and secreted by the organism and very difficult to eradicate 7,136-140.

Catheter-related bacteremia can result in devastating complications such as endocarditis, osteomyelitis, thrombophlebitis, septic arthritis, spinal epidural abscess, and large atrial thrombi 30,31,141-149. The majority of isolated organisms from catheter-related bacteremia are gram-positive organisms (52-84%) with *Staph Aureus* responsible for the majority of these organisms 7,30,31,143,150,151. Gram-negative are isolated in 27-36% of episodes and fungal isolated are relatively uncommon (<10%) 141-143,149,152. Therefore, it is important to identify catheter-related bacteremia early so treatment can be initiated immediately.

### **4.2.1 Treatment of catheter-related bacteremia**

Initial empiric antibiotic treatment should include broad-spectrum coverage for grampositive and gram-negative organisms using knowledge of the common organisms and

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

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,

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

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

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.

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

stenosis remains questionable.

**5.2 Radiation therapy** 

**5.3 Far infrared therapy** 

unassisted patencies 190.

sirolimus 177, and imatinib mesylate 176,178,179.

improvement in secondary patency at either 6 or 12 months 186.

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

**5.4.1 Drug eluting paclitaxel perivascular wraps** 

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 prophylactic catheter lock 165.

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 complications 7.
