臺灣博碩士論文加值系統

研究背景
　　貧血是慢性腎臟病患者常見的併發症，決定腎功能不全患者預後及生活質量的重要因素，而末期腎臟病患者貧血的狀況更為嚴重。一般而言，末期腎臟病患者貧血類型為典型的正色正球性貧血（normocytic and normochromic anaemia），但是有高達30%的透析患者有巨紅血球症（macrocytosis），可能的原因為葉酸缺乏所致，因此對末期腎臟病患者而言貧血伴隨巨紅血球症死亡風險可能提高。甲烯基四氫葉酸還原酶（Methylene tetrahydrofolate reductase, MTHFR）是參與葉酸單碳循環及同半胱胺酸代謝的關鍵酵素，在DNA的合成細胞增殖和DNA甲基化中起關鍵作用，MTHFR基因的編碼直接調控甲烯基四氫葉酸還原酶，C677T基因位點發生突變時會降低MTHFR酶的活性。
研究目的
　　本研究欲探討巨球性貧血及MTHFR基因多型性與血液透析患者死亡風險之相關性。
研究方法
　　本研究採回溯性世代研究，自2015年12月至2017年8月收集三總等七家洗腎門診的血液透析病患且腎絲球過濾率(eGFR)小於15 mL/min/1.73 m2 ，並排除血色素正常(Hemoglobin,Hb)>13b/dL(男性)、Hb>12b/dL(女性)，及80歲以上個案，共534人，並取得結構式問卷、病歷資料，以平均血球容積(mean corpuscular volume, MCV)大於100fL定義巨球性貧血（macrocytic anemia），並進行基因型分析。利用SPSS 22.0版及R統計軟體進行統計分析。
研究結果
　　追蹤20.5個月之後，血液透析患者死亡共99人，其中巨球性貧血比例佔20.2%。以Cox比例風險模型估算血液透析病患罹患巨球性貧血之死亡風險是罹患非巨球性貧血的2.08倍(Adj-HR=2.08; 95% CI: 1.23 - 3.52)。性別分層後，女性罹患巨球性貧血的死亡風險是罹患非巨球性貧血的2.89倍(Adj -HR=2.89; 95% CI: 1.54 - 5.41)。MTHFR C677T基因多型性與血液透析病患全死因及死因別死亡風險無統計上顯著相關。
結論
　　巨球性貧血與血液透析病患全死因死亡風險及感染死亡風險顯著相關，且對女性而言死亡風險更高。因此未來研究可進一步釐清其中之因果關係，可做為血液透析患者死亡之預防策略。

Background: Anemia is a common complication condition in patients with chronic kidney disease (CKD), especially for those with a moderate to severe stage of CKD. In general, the anemia of end-stage renal disease(ESRD) is typically normocytic and normochromic, but up to 30% may have macrocytosis. Proposed causes of macrocytosis in dialysis patients due to B12 and folate deficiency.However, the association of macrocytic anemia with mortality in hemodialysis patients is unkown.In the folic acid cycle, MTHFR catalyzes formation of methyltetrahydrofolate, which donates a methyl group to homocysteine to produce methionine. The MTHFR C677T single nucleotide polymorphism is associated with decreases in MTHFR enzyme activity.
Aim:The purpose of this study is to determine whether the macrocytic anemia or MTHFR C677T polymorphisms independently affect survival of patients with ESRD.
Method: Our retrospective cohort study included 534 chronic hemodialysis patients with anemia(hemoglobin>13b/dL,male;hemoglobin>12b/dL,female) receiving chronic hemodialysis from five clinics and one medical center in Taipei and New Taipei city, Taiwan. Macrocytic anemia was defined as a mean corpuscular volume (MCV) > 100 fl. The independent association of macrocytic anemia and MTHFR C677T polymorphisms with mortality was examined by multivariate Cox regression analysis.
Results: Among 534 participants, 99 patients died (20.2% with macrocytic anemia) during follow-up 20.5 months. In the adjusted multivariable cox regression models, macrocytic anemia was 2.08 folds higher mortality than non-macrocytic anemia (Adj-HR=2.08; 95% CI: 1.23 - 3.52). Especially, macrocytic anemia was associated with higher mortality(Adj -HR=2.89; 95% CI: 1.54 - 5.41) in women. The overall relationship between the C677T polymorphism and mortality was not significant.
Conclusion: Macrocytic anemia was associated with all-cause mortality and infection-associated mortality. The underlying pathophysiologic mechanisms used futher investigation.

摘要 7
Abstract 9
第一章 前言 11
第一節　研究背景 11
第二節　研究動機與重要性 13
第三節　研究目的 15
第二章　文獻探討 16
第一節　貧血與末期腎臟病 16
第二節　貧血與葉酸缺乏之巨紅血球症 20
第三節　甲烯基四氫葉酸還原酶與葉酸代謝 22
第四節　MTHFR基因多型性與末期腎臟病 24
第三章　研究方法 26
第一節　研究設計及研究架構 26
第二節　資料收集與定義 27
第三節　統計方法 33
第四章　研究結果 35
第一節　研究個案之基本人口學及血液生化值 35
第二節　不同貧血類型之血液透析患者基本人口學及血液生化值差異 40
第三節　探討影響血液透析病患基本人口學與血液生化值之死亡風險 47
第四節　不同貧血類型血液透析病患與全死因及死因別死亡風險之相關性 52
第五節　MTHFR C677T基因多型性之基本人口學及生化檢查值差異 65
第六節　MTHFR C677T基因多型性與血液透析病患全死因及死因別死亡風險之相關性 72
第七節　MTHFR C677T基因多型性與血液透析病患巨球性貧血之相關性 79
第五章　討論 83
第一節　研究族群基本人口學變項及血液生化值 83
第二節　巨球性貧血與血液透析病患死亡 86
第三節　MTHFR C677T基因多型性與血液透析病患死亡 90
第四節　血液透析病患罹患巨球性貧血的原因 92
第五節　本研究限制 95
第六章　結論 96
第七章　建議 97
參考文獻 98
附錄 104

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