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本研究是建立一個以免疫研究的末期腎病世代。我們收集病患每週透析前的血液，血色素、白血球計數，血中生化指數包括尿素氮、肌肝酸、白蛋白、總膽固醇、三酸甘油脂，鈣、磷，並計算透析廓清率（簡稱Kt/V）標準化蛋白質異化速率（簡稱nPCR）來評估透析適量及蛋日質攝取狀況。周邊血單核細胞也同時收集並染色並由流式胞儀分類判讀。血漿中發炎胞激素（TNF-α 和 IL-6）亦會測定。周邊血單核細胞經由細胞表抗體分不同細胞種類。本研究將T細胞分為四大類：初始T細胞(Tnaive), 中央記憶型T細胞 (TCM), 作用記憶型T細胞 T cell (TEM) 和再表現CD45RA之終端作用型T 細胞 (TEMRA)。各式免疫細胞資料的判讀是由多色相流式細胞儀協助。
收集412位末期病患加入本研究，408位病患是曾經被巨細胞病毒（Cytomegalovirus, HCMV）感染，經由和57位健康測試者比對，透析患者有較高的巨细胞病毒免疫球蛋白(anti-HCMV IgG)。在多重迴歸分析下且調整年紀、性別、血色素、糖尿病、鈣磷乘積和高敏感反應蛋白(hs-CRP)，既存心血管疾病和取對數的巨细胞病毒免疫球蛋白(anti-HCMV IgG)的血中濃度有獨立相關性(OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01)。巨细胞病毒的免疫球蛋白(anti-HCMV IgG)的值和終端分化的CD8+ and CD4+中再表現CD45RA之終端作用型T 細胞 (TEMRA)的細胞比例及絕對細胞數有顯著的的正相關，意味著免疫老化在心血管疾病的發展扮演重要角色。而我們前導實驗，發現由IL-1β誘導的3T3-L1 脂肪細胞，模仿PFY著胰島素阻抗，可發現發炎反應中Plasma leucine-Rich α 2-glycoprotein 1 (LRG1)有上昇的反應。在本研究中血中LRG-1和IL-6, hsCRP呈正相關，而在單一變項迴歸分析，LRG1和心血管疾病及週邊動脈血管疾病中有顯著的的相關。在多重迴歸分析下且調整年紀、性別、血色素、糖尿病、鈣磷乘積和高敏感反應蛋白(hs-CRP)，LRG1分三組後愈高的組別和週邊動脈疾病 (odds ratio = 3.49) 和心血管疾病(odds ratio = 1.65) 有顯著的風險增加。
|dc.description.abstract||Background: Many adverse pathophysiological changes including infection, inflammation, atherosclerosis, and premature mortality is associated with End-stage renal disease (ESRD). Traditional risk factors as well as non-traditional risk factors, such as inflammation, are believed to contribute to the excessively heavy burden of cardiovascular disease in ESRD patients. The pro-inflammatory microenvironment is collectively caused by uremic milieu, infection, and tissue ischemia even before the initiation of dialysis. We established a cohort-base study to explore virus infection and inflammation -related adverse outcome.|
Method: This analysis is based on the subjects enrolled in the Immunity in ESRD. We collected peripheral blood samples at the beginning of hemodialysis during the first session of the week. Hemoglobin level, white blood cell counts, blood biochemistry including blood urea nitrogen (BUN), creatinine, albumin, total cholesterol, triglyceride, calcium, and phosphate were measured. Kt/V and normalized protein catabolic rate (nPCR) were calculated to represent dialysis adequacy and dietary protein intake. Peripheral blood mononuclear cells (PBMCs) were isolated and submitted for flow cytometry analysis. LRG1 was measured by ELISA. The plasma levels of inflammatory cytokines, TNF-α and IL-6, were assayed respectively. We obtained peripheral blood mononuclear cell (PBMC) to identify distinct cell types based on surface marker. The expression patterns of specific T cell subsets in progressive differentiation status are as the following: Naïve T cells (Tnaive), central memory T cells (TCM), effector memory T cell (TEM) and terminal effector T cells with CD45RA re-expression(TEMRA). Data acquisition was performed using a multicolor flow cytometer.
Result: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ T EMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. Our pilot study found that Plasma leucine-Rich α 2-glycoprotein 1 (LRG1) is linked with inflammatory response via an IL-1β-treated 3T3-L1 adipocyte model. The level of LRG1 had a positive correlation with IL-6, hsCRP in our cohort . In the univariate analysis, a higher level of LRG1 was associated with the presence of cardiovascular disease (CVD) and peripheral arterial occlusive disease (PAOD). In multivariate logistic regression models, higher LRG1 tertile was significantly associated with PAOD (odds ratio = 3.49) and CVD (odds ratio = 1.65), but not with coronary artery disease, history of myocardial infarction, or stroke after adjusting for gender, diabetes, hemoglobin, albumin, calcium-phosphate product, and level of hsCRP.
Our current study is the first to demonstrate that anti-HCMV IgG titer is elevated in ESRD patients with persistent HCMV infection and associates with coronary artery disease. The effect is significant and independent of traditional and non-traditional cardiovascular risk factors. Level of HCMV IgG also positively correlates with T cell terminal differentiation, which could serve as the mediator for this association.
LRG1 level is independently associated with higher prevalence of peripheral arterial occlusive disease(PAOD) and cardiovascular disease (CVD) in ESRD patients treated with hemodialysis. The level of plasma LRG1 is also significantly correlated with inflammation, represented by IL-6 and hsCRP levels, which contributes to the development of cardiovascular pathology.
Further investigation about HCMV reactivation and LRG1 with cardiovascular risk should be considered and the possible mechanism about infection and inflammation is warranted to explorer in this susceptible population.
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Previous issue date: 2020
Abstract (Chinese) 3
Table of Contents 8
Chapter 1 Introduction 12
1. 1 Cardiovascular disease in End-Stage Renal Disease 12
1. 1. 1 End stage renal disease: epidemiology and complications 12
1. 1. 2 The prevalence of cardiovascular disease in ESRD 12
1. 1. 3 Risk Factors of cardiovascular disease in ESRD 13
1. 2 Innate and adaptive immunity dysfunction in end stage renal disease 15
1. 2. 1 Innate Immunity System 15
1. 2. 2 Adaptive Immune System 16
1. 2. 3 Immune system in ESRD 17
1. 3 Inflammation in end stage renal disease 17
1. 3. 1 Disturbances of the inflammation in ESRD 18
1. 3. 2 Association between the uremia related immune dysfunction in inflammation, infection, and CV risk 18
1. 4 Virus infection related CVD in ESRD 18
1. 5 Metabolic syndrome and inflammation 20
1. 5. 1 Adipokines and inflammation 20
1. 5. 2 Discovery from IL-1β-treated 3T3-L1 adipocyte: LRG1 22
1. 6 LRG1 role from metabolic factor to CVD in ESRD 23
1. 7 Hypothesis with study goal and specific aims 24
Chapter 2 Subjects, materials and methods 26
2. 1 Clinical research 26
2. 1. 1 Participants -our cohort: iESRD 26
2. 1. 2 Clinical Biostatistics: Data collections and laboratory exams 27
2. 1. 3 Clinical Biostatistics: Coding book 28
2. 1. 4 Cardiovascular co-morbidities 29
2. 2 Basic research 30
2. 2. 1 Multicolor flow cytometry 30
2. 2. 2 Isolation of Human PBMC from Whole Blood 30
2. 2. 3 Immunophenotyping :T cell differentiation 33
2. 2. 4 Immunophenotyping : Monocyte staining 34
2. 3 Statistical analyses 34
Chapter 3 Results 37
3. 1 The role of HCMV in ESRD 37
3. 1. 1 Baseline characteristics of study population 37
3. 1. 2 HCMV IgG levels in ESRD 37
3. 1. 3 Elevated HCMV IgG levels is not associated with systemic inflammation in ESRD 38
3. 1. 4 Higher CMV-IgG level is associated with advanced T cell differentiation but not monocyte subset distribution in ESRD 39
3. 1. 5 Cardiovascular co-morbidities stratified by HCMV IgG levels 40
3. 1. 6 HCMV IgG level independently associates with prevalent CAD 41
3. 2 The role of LRG1 in ESRD 41
3. 2. 1 Patient demographics and clinical characteristics 41
3. 2. 2 Plasma LRG1 levels in ESRD patients 41
3. 2. 3 Elevated plasma LRG1 is associated with systemic inflammation in ESRD 42
3. 2. 4 Higher LRG1 is associated with lower central memory T cells in ESRD 42
3. 2. 5 The frequency of cardiovascular comorbidities stratified by plasma LRG1 levels 43
3. 2. 6 Plasma LRG1 level is independently associated with PAOD and prevalent CVD 44
Chapter 4 Discussion 44
4. 1 HCMV infection in ESRD 45
4. 1. 1 HCMV infection related CVD in ESRD 45
4. 1. 2 HCMV infection related advanced T cell differentiation in ESRD 45
4. 1. 3 HCMV infection related CV events in ESRD 46
4. 1. 4 Limitations and summary of HCMV infection related CV events in ESRD 47
4. 2 LRG1 in ESRD 48
4. 2. 1 LRG1 with T cell in ESRD 48
4. 2. 2 LRG1 with inflammation marker in ESRD 49
4. 2. 3 LRG1 with angiogenesis in ESRD 50
4. 2. 4 LRG1 with PAOD in ESRD 50
4. 2. 5 Limitations and summary of LRG1 related CV events in ESRD 51
Chapter 5 Future perspectives 52
5. 1 The trajectory of HCMV IgG for 5-year cohort 54
5. 2 HCMV related polyfunctionality in ESRD 56
Chapter 6 Tables and Figures 57
Table 1. Two-year survival of patients with a prevalent cardiovascular disease, by CKD status, adjusted for age and sex, 2015-2016 57
Table 2. Differences of Innate and Adaptive immunity 58
Table 3. Disturbances of the immune system in ESRD patients 59
Table 4. Characteristics of three chronic infection associated with vascular disease 60
Table 5. Summary of local mechanisms in chronic infections 61
Table 6. Baseline demographic data of iESRD participants 62
Table 7. Baseline demographic, clinical and laboratory measurements stratified by HCMV-specific IgG titer 63
Table 8. Correlations between log transformed HCMV-specific IgG titer with levels of immune cells among healthy individuals 64
Table 9. Correlations between HCMV-specific IgG titer with levels of immune cells among ESRD patients 65
Table 10. Associations between HCMV-specific IgG quintile with coronary artery disease and cardiovascular disease 66
Table 11. Associations between log-transformed HCMV-specific IgG level with coronary artery disease and cardiovascular disease 67
Table 12. Baseline demographic, clinical and laboratory parameters stratified by plasma LRG1 level in ESRD patients 68
Table 13. Correlations between plasma LRG1 concentration and immune cell levels in ESRD patients 69
Table 14. Associations between plasma LRG1 tertile with peripheral arterial occlusive disease (PAOD) and cardiovascular disease (CVD) 70
Table 15. Associations between plasma LRG1 concentration with peripheral arterial occlusive disease (PAOD) and cardiovascular disease (CVD) 71
Figure 1 Incidence rate of ESRD, by country, 2016 72
Figure 2 Average yearly change in ESRD prevalence rate (2003-2016) 73
Figure 3 CVD mortality in ESRD and general population 74
Figure 4 Prevalence of cardiovascular diseases in adult ESRD patients, by treatment modality, 2016 75
Figure 5 Factors in cardiovascular disease for ESRD patients 76
Figure 6 Mutiple risk Factors in cardiovascular disease for ESRD patients. 77
Figure 7 Summarized CV risk factor in ESRD patients 78
Figure 8 The central role of inflammatory cells (macrophages and lymphocytes) in uremic atherogenesis 79
Figure 9 Association between the uremia related immune dysfunction in inflammation, infection, and CV risk 80
Figure 10 Possible impact of an impaired immune function in uremia on mortality. 81
Figure 11 Life of HCMV Infection 82
Figure 12. IL-1β-treated 3T3-L1 adipocyte model is to mimic the cells in a insulin resistant condition and inflammation 83
Figure 13. Hypothesis with study goal and specific aims 84
Figure 14 Levels of HCMV-specific IgG and T cell gating 85
Figure 15. Trend of patients with co-morbidity among each HCMV-IgG quintile 86
Figure 16 Percentage of patients with co-morbidity among HCMV-IgG quintile 87
Figure 17 Correlations between plasma LRG1 and other markers of inflammation in ESRD patients 88
Figure 18 Prevalence of cardiovascular comorbidities stratified by plasma LRG1 level in ESRD patients 89
Figure 19 Prevalence of cardiovascular comorbidities stratified by hsCRP level 90
The conclusion of our study 102
|dc.title||The relationship between Immune - inflammation and cardiovascular disease in End-Stage Renal Disease||en|
|dc.contributor.oralexamcommittee||吳彥雯(Yen-Wen Wu),邱彥霖(Yen-Ling Chiu),姜至剛(Chih-Kang Chiang)|
|dc.subject.keyword||end-stage renal disease,human cytomegalovirus,cardiovascular disease,Leucine-rich α-2-glycoprotein 1,inflammation,peripheral arterial disease,||en|
|Appears in Collections:||臨床醫學研究所|
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