1.1 Arteriovenous Fistula Stenosis
Autologuos arteriovenous fistula (AVF) is universally recommended to be the first choice of long term vascular access for patients receiving hemodialysis 1-3. Many national guidelines suggest AVF for hemodialysis in terms of infection, patient quality of life and medical costes. The maintenance of AVF patency remains a challenge to current medicine in terms of stenosis. Several advances had been made to facilitate the maintenance of AVF patency. These included ultrasound assessment for operation, proper timing for 1st catherization, catherization technique, far infrared therapy 4,5. Even with those approaches detailed in some guidelines for vascular access creation and care, the AVF stenosis rates were still far from optimal. According to a recent systemic review, the 1-year patency rates were reported 62~68%, and 2-year patency rates were 38~56% excluding primary failure6 .
To overcome the difficulty, the physiological mechanisms of AVF stenosis were widely studied and proposed to be affected mainly by intimal hyperplasia and inappropriate outward remodeling 7. On the basis of these understandings, some medications possessing potential beneficial effect on AVF patency such as ACEI, AIIA, anti-platelets, anti-coagulants had been tested in clinical studies 8-10, but no medication had been consistently reported to possessing beneficial effect on AVF patency.
Among the candidate medicine for improving AVF stenosis, statins received special scrutiny. Statins are well known to reduce inflammation
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and improve endothelial function beyond cholesterol lowering in end stage renal disease patients. In animal studies, statins had been demonstrated to improve blood flow, endothelial function and prevent stenosis of AVF which may result from attenuating the activity of proinflammatory genes and oxidative stress in the remodeled vasculature
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. Though possessing potential protection effects on AVF patency, statins had never been proved to be protective from AVF stenosis in a large human dialysis patients study. Some studies reported that statins were not associated with improved survival of vascular access in dialysis
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, while one small number study showed that it was beneficial 17. There is no one medication having as more discrepant results as statins between basic researches and clinical studies. To fill up the gap, one part of this thesis was aimed to evaluate the effect of statins on the AVF long term patency through a nation-wide population cohort study.
1.2 Glomerulonephritis and Oxidative Stress
Glomerulonephritis(GN) is a constellation of heterogenous renal diseases featured as a shared pathophsiology of immune mediated glomerular inflammation 18,19. Despite some of these patients may benefit from specific immunosuppressive therapies, many others who are irresponsive to the management eventually develop ESRD 20-23. Glomerulonephritis is one of the leading causes of ESRD and remains a medical challenge today 24. Implementation of more interventions shown to be effective to cure or slow down the progression of GN is very important from both public health and economic point of view. Stem cells
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had been proved the potential of self-renewal and the ability of immune modulation and provide one potential therapeutic option to the unmet need of those GN patients 25.
Mesenchymal stem cells (MSC) had been demonstrated to improve renal function in animal GN models studies 25, and in some refractory human lupus nephritis studies 26,27. MSC therapy improves renal function and decreases severity of glomerulosclerosis through direct differentiating into renal cells and paracrine effects. The evidence suggests that the direct contribution of transplanted cells to tissue regeneration is minimal 28. The paracrine effects are believed to play a major role in the therapeutic effect to damaged kidney 19. Stem cells cross talk with target organs by secreting growth factors, cytokines and prostaglandins, which regulate anti-inflammation, anti-apoptosis, and anti-fibrosis effect to enhance cell proliferation, survival and angiogenesis to repair injuried tissue.
In glomerlonephritis, increased oxidative stress contributes to the pathogenesis of mesangial proliferative GN leading to renal dysfunction
29. MSC had been shown to possess anti-oxidative effect which plays a role an important role in the treatment of GN 30. Compared with the anti-inflammatory, immune modulatory effects, the mechanisms underlying protection of MSC from oxidative injury in the therapeutic effect on GN remain scarcely elucidated. Hypoxic preconditioning is a promising strategy to improve efficacy of stem cell therapy. Under hypoxic condition, MSC can not only prevent senescence, increase differentiation efficiency but also enhance stem cell homing 31,32. But
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there is little knowledge about how hypoxic pre-condition affect the anti-oxidative effect. The another part of the present thesis aimed to investigate the anti-oxidative stress mechanisms involved in the use of mesenchymal stem cells and hypoxic mesenchymal stem cell in the GN rat model.
The growing end stage renal disease (ESRD) population and expanding cost of renal replacement therapy (RRT) have great burden on both public health and economics. Both to develop effective treatment for GN and to improve ESRD patient care are important for management of the growing problem. However, high stenosis rates of AVF and limited available treatment of GN remained medical challenges today. This thesis was to explore the medical preventive strategy of AVF stenosis and the anti-oxidative therapeutic mechanism of stem cell on GN through population based and animal model studies.
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