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研究生:詹正雄
研究生(外文):Jenq-Shyong Chan
論文名稱:血中氧化壓力指標對於血液透析瘻管急性栓塞以及是否容易狹窄性功能不良的預測
論文名稱(外文):The Role of Oxidative Stress Markers in Prediction of Hemodialysis Vascular Access Acute Thrombotic Occlusion and Progressive Stenotic Dysfunction Demand Angioplasty
指導教授:施俊哲施俊哲引用關係
指導教授(外文):Chun-Che Shih
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:英文
論文頁數:40
中文關鍵詞:基質金屬蛋白酶基質金屬蛋白酶基質金屬蛋白酶
外文關鍵詞:hemodialysis vascular accessmatrix metalloproteinaseasymmetrical dimethylarginine
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中文摘要
背景:
血液透析廔管急性栓塞或因血管狹窄導致廔管功能不良,是為尿毒症病人住院及死亡合併症常見的原因。突發性靜脈端血栓性阻塞和經皮血管整形術後反覆發生再狹窄是透析瘻管長久使用的二大絆腳石。由先前研究已知:尿毒症患者血中的一些氧化壓力指標上升與血管內皮細胞功能不良進而導致心血管疾病常發生有關。目前並不知道這些氧化壓力指標,能否也可用來預測瘻管急性血栓性阻塞的發生以及功能不良需作經皮血管整形術的關聯性。

方法:
利用酵素連結免疫吸附法來測得所選的血中氧化壓力指標如:高敏感度C反應蛋白、基質金屬蛋白酶第2、9型、同半胱胺酸、非對稱性二甲基精胺酸、一氧化氮等共六項。分析159位血液透析病患(其中83位男性、76位女性,平均年齡65歲±12年),所有病人規則接受每週三次每次四小時的血液透析,透析維持超過6個月以上未接受任何廔管重建或侵入性血管治療。這些病人在計劃執行追蹤的12個月內,分別記錄突發性廔管靜脈端血栓性阻塞和廔管功能不良而需接受經皮血管整形術的2個中止觀察點。

結果:
在為期一年的觀察,共有24位病人(佔159位中的百分之15)發生原發性瘻管急性血栓性阻塞;另外24位病人(佔159位中的百分之15),因透析瘻管功能不良(符合美國2006年DOQI血液透析瘻管指引四的定義),而需執行經皮血管整形術治療,在手術後持續追蹤出現再次狹窄(功能不良)的有12位,佔原24位中的百分之50。
第一組為比較急性瘻管血栓性阻塞者與無發生急性瘻管血栓性阻塞者之間:血中基礎值的氧化壓力指標(高敏感度C反應蛋白、基質金屬蛋白酶第2、9型、同半胱胺酸、非對稱性二甲基精胺酸、一氧化氮,等六項)均無明顯有統計上的差異;但是若瘻管型式為聚四氟乙烯(PTFE)之人工血管病患及存有週邊動脈阻塞疾病病史診斷者,兩項有統計上的差異,可作預測瘻管容易產生急性血栓性阻塞的指標(危險比分別為16.9及2.35,P值各為小於0.001及0.047)。
第二組觀察在比較透析瘻管功能不良(符合DOQI血液透析瘻管指引第四項)需接受經皮血管整形擴張術者與透析瘻管功能維持正常者的結果:在66位血中非對稱性二甲基精胺酸基礎濃度大於0.6207μM 者,其中的百分之27病人因瘻管功能不良而需接受經皮血管整形術擴張,相對於非對稱性二甲基精胺酸基礎值小於等於0.6207μM的89位中,僅有百分之4.5會因瘻管功能不良而需接受經皮血管整形術擴張。於多變項分析中:非對稱性二甲基精胺酸的基礎血液濃度可作為預期透析瘻管功能不良而需要作血管整形術擴張的唯一有意義指標(適用於自體或人工吻合的透析瘻管),(危險比為7.13,P值小於0.001)。

結論:
在本研究結果得到:人工合成(聚四氟乙烯)的血液透析瘻管相較於自體動靜脈吻合的血液透析瘻管易常發生急性血栓性阻塞。對於血液透析病患是否具有診斷週邊動脈阻塞疾病者,可為預期日後透析期間容易發生急性瘻管血栓性阻塞。而血中氧化壓力指標的非對稱性二甲基精胺酸的高低,則可作為瘻管容易產生狹窄性功能不良而需使用經皮血管成形術治療的預測,未來也可針對此一血管氧化壓力指標的濃度改變,研究出可拮抗之藥物,以期減少病人瘻管狹窄性功能不良的產生,進而延長血液透析瘻管使用的年限。

ABSTRACT
Background: Hemodialysis vascular access dysfunction is a major cause of morbidity among hemodialysis (HD) patients. Primary venous outflow occlusion and restenosis after percutaneous transluminal angioplasty (PTA) are two major obstacles for the long term use of dialysis vascular access. Increased levels of circulating oxidative stress markers correlate with vascular endothelial dysfunction and development of cardiovascular events in uremia patients. It is not known whether these oxidative stress markers can be used as predicators for the thrombotic occlusion of vascular access (VA) and the progressive stenosis dysfunction demand percutaneous transluminal angioplasty (PTA).

Methods: Circulating levels of oxidative stress factors: hsCRP (high-sensitivity c-reactive protein), MMP-2 (matrix metalloproteinase), MMP-9, Homocysteine and ADMA (asymmetrical dimethylarginine) and NO (nitrate oxidase) were measured by immunosorbent assay ( ELISA) in 159 HD patients ( 83 male, 76 female, mean age: 65±12 ), All patients had been stabilized on renal replacement therapy for >6 months and were free of active infection. Patients were followed up clinically for up to 12 months to estimate the amount of the primary thrombotic occlusion and vascular access dysfunction demand PTA.

Results: During the 12 months observation, 24 patients (15.1%) experienced primary thrombotic occlusion of vascular accesses. Another 24 patients (15.1%) need to undergo the PTA owing to clinical dysfunction of access. Also during the follow-up period, restenosis occurred 12 patients (50% of 24 patients). There are no difference of oxidative stress factors (hs-CRP, MMP-2, MMP-9, ADMA, homocysteine and NO) level between acute thrombotic occlusion and non-thrombotic occlusion. But access types of AVG (arteriovenous graft) and diagnosed with peripheral artery occlusive disease (PAOD) are two strong predictors for acute thrombotic event of vascular access (hazard ratio HR: 16.9 vs 2.35, P <0.001 vs 0.047). In the comparison dysfunction with non-dysfunction vascular accesses, up to 27.3% of the patients with high levels of ADMA (>0.6207 μM, N=66) had been necessarily received PTA compared with 4.5% of those with low levels (≦0.6207 μM, N=89; P<0.001). In multivariate analysis, plasma baseline levels of ADMA are independently nearly seven times the risk of primary stenostic dysfunction of hemodialysis vascular access ,(hazard ratio 7.13; 95% confidence interval 2.41 to 21.07)

Conclusion: The AVG is easily thrombotic events than the AVF (arteriovenous fistula) in our study. To recognize and early detection the PAOD in the hemodialysis patients is very important thing due to PAOD can used to predict whether it is easily or not in the acute thrombotic occlusion of vascular access from our study in the further clinical practice. Also, these results suggest a role for oxidative stress markers ADMA in the development of symptomatic dysfunction of VA in hemodialysis patients and call for preventive strategies that target endothelial dysfunction to decrease the risk of vascular access progressive stenosis.

目錄 ( Contents )
Acknowledgement...........................................1
English abstract…………………………… …3
Chinese abstract……………………………………………………..6
Abbreviations………………………………………………………...8
Chapter 1. Introduction…………….……………… ………....9
Chapter 2. Materials and Methods…………………………… ..11
Chapter 3. Result……………………………… ..……………….18
Chapter 4. Discussion……………………………….…………...23
Chapter 5. Conclusion…………………………… …………..28
Chapter 5. References……………………….…………..……….29
Chapter 6. Tables……………………… .…………….……. ….32
Figures…………………………………………… ….37

REFERENCES
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8.Wu CC, Wen SC, Yang CW, Pu SY, Tsai KC, Chen JW. Plasma asymmetrical dimethylarginine predicts symptomatic arteriovenous fistula restenosis after angioplasly. J Am Soc Neprology 2009; 20: 213-22.
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