**3.2.3 Endothelial dysfunction**

An intact and functional endothelium is essential for the vein to properly respond to acute changes in blood flow that occurs after creation of AVFs and AVGs 98. Nitric oxide (NO) is an important mediator responsible for these transformations 99,100. The presence of uremia in hemodialysis patients has been shown to exacerbate endothelial dysfunction, possibly through the pathways of inflammation and oxidative stress described above 101,102. In the specific context of vascular access stenosis, endothelial dysfunction is likely to be responsible for the development of pre-existing venous neointimal hyperplasia 77-81, medial hypertrophy 77,81 and radial artery intima-media thickening 103-105 that is present even before the creation of AVFs in uremic patients. Pre-existing arterial intima-media thickness has been correlated with future AVF dysfunction 103. Recently, pre-existing venous neointimal hyperplasia has been linked to poor AVF maturation in a small clinical study 77.

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase and has been implicated as an important contributor to endothelial dysfunction in ESRD patients 106. ADMA is not excreted in ESRD patients and its levels have been reported to be two to six times higher in this patient population as compared to non-uremic individuals 107. In a recent clinical study in AVFs, patients with elevated ADMA levels at the time of percutaneous transluminal angioplasty of an initial AVF stenosis had a significantly increased risk of a recurrent AVF stenosis 108.

### **3.2.4 Alternative origins of neointimal cells**

Although the traditional paradigm for the pathogenesis of neointimal hyperplasia has emphasized the migration of smooth muscle cells from the media to the intima, where they proliferate and contribute to the final volume of neointimal hyperplasia, a number of studies have reported that following coronary angioplasty or saphenous vein bypass grafting there is also a migration of cells (fibroblasts) from the adventitia, through the media, and into the intima, where these cells transform into "myofibroblasts" 109-111. In dialysis access, a number

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

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

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

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

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

catheter-related bacteremia early so treatment can be initiated immediately.

heparin had reduced incidence of catheter dysfunction 34.

**4.2 Catheter-related bacteremia** 

catheter in a symptomatic patient 134.

the organism and very difficult to eradicate 7,136-140.

**4.2.1 Treatment of catheter-related bacteremia** 

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 targeting specific cell types.
