系統識別號 U0026-1308201514253600
論文名稱(中文) 台灣的糖尿病、腎臟病及不同克雷白氏肺炎菌感染之間的影響機轉
論文名稱(英文) The Complex Interplay among Diabetes Mellitus, Chronic Kidney Disease and Different Klebsiella pneumoniae Infections in Taiwan
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 林威宏
研究生(英文) Wei-Hung Lin
電子信箱 dindonwhlin@hotmail.com
學號 S98981131
學位類別 博士
語文別 英文
論文頁數 140頁
口試委員 指導教授-吳俊忠
中文關鍵字 克雷白氏肺炎菌  糖尿病  尿道感染  末期腎病變 
英文關鍵字 K. pneumoniae  diabetes mellitus  urinary tract infection  end stage renal disease 
中文摘要 在社區環境之中,克雷白氏肺炎菌是一個會引起各種臨床感染包括菌血症、肺炎、尿道感染、腦膜炎以及各處膿瘍的致病菌。其中克雷白氏肺炎菌引起的社區型感染菌血症伴隨肝膿瘍,是一個在台灣相當被重視的臨床症候群。我的博士論文就是從國家健康保險資料庫去分析糖尿病是克雷白氏肺炎菌引起的肝膿瘍中,所扮演最重要的角色。從大型的世代研究,可以證實過去所研究的糖尿病與肝膿瘍罹病風險的關聯性。這樣的研究發現此風險存在於較為年輕的糖尿病病人,而且當伴隨膽道疾病或者肝硬化時,會有更高的罹患肝膿瘍風險,因此需要在診治糖尿病病人時,及早做預防和注意。基於對於流行病學研究的了解,我們發現糖尿病、肝膿瘍以及克雷白氏肺炎菌之間的緊密關聯性。為了能夠更深入研究,我建置了一個全國於1999年至2010年之間診斷為第一型糖尿病的台灣大型世代資料。這個於全篇論文所用來分析的世代族群是來自於臺灣的健保資料庫,並提供準確且代表全國第一型糖尿病病人的登錄資料。我先用此來研究第一型糖尿病在性別年齡分層的長期發生率趨勢,以及相對應的死亡率。我也用此世代資料觀察長期罹患末期腎病變的風險,並且檢視發病年齡、罹病時間以及性別對於發生末期腎病變的影響。
英文摘要 In the community setting, Klebsiella pneumoniae is a potential pathogen with various clinical manifestations, including septicemia, pneumonia, urinary tract infection (UTI), meningitis, and purulent abscesses at various sites. In particular, a distinctive clinical syndrome, which is characterized by community-acquired K. pneumoniae bacteremia with primary liver abscess has been recognized in Taiwan. My PhD research started from National Health Insurance Research Database (NHIRD) to analyze the role of diabetes mellitus (DM) as most important host factor in pyogenic liver abscess (PLA) caused by K. pneumoniae. The large-scale cohort study confirmed the previously reported link between diabetes and risk of PLA onset. This study advanced the knowledge highlighting a stronger association noted for younger patients; and that diabetic patients with underlying biliary tract diseases and liver cirrhosis are at even greater risks of PLA onset and should be the objects of particular attention for the prevention of PLA onset in patients with diabetes. Based on the knowledge of our epidemiologic study, we found the close association between DM, PLA and K. pneumoniae. To be investigated more deeply, I constructed a large population-based type 1 diabetes mellitus (T1DM) cohort in Taiwan diagnosed between 1999 and 2010. The data analyzed in my thesis were derived from Taiwan’s NHIRD that provides a valid and nation-wide registration system for T1DM. I investigated the long-term trends of incidence rate of T1DM in all sex and age stratifications and to explore the overall as well as the age and sex-specific risk of mortality in patients with T1DM. I also investigated the long-term risk of end stage renal disease (ESRD) in patients with T1DM and examined how age at registration of diabetes, time period of registration, and sex affect these risks.
At the same time, I enrolled all the K. pneumoniae strains at National Cheng Kung University Hospital since 2006 to survey the clinical and microbiological characteristics in UTI, abscess and peritoneal dialysis (PD)-related infections. First, I investigated the expression of hypermucoviscosity (HV) and the presence of the virulence gene of K. pneumoniae in UTI strains including the association of host factors, especially DM, with K. pneumoniae associated UTI. Second, I evaluated the host and bacterial characteristics of K. pneumoniae in recurrent UTI (RUTI). The results demonstrated all the RUTI occurred in DM patients. Third, I studied the change in distribution of causative organisms in PD-related peritonitis during a 22-year period. I investigated the microbiological characteristics of K. pneumoniae and host factors in PD-related peritonitis such as old age, DM or immunocompromised status to predict critical case for clinical therapy. Finally, I screened a novel adhesion gene, KPN_2990, from my uropathogenic K. pneumoniae and investigated the role in K. pneumoniae UTI by mutant construction with inflammatory cytokines analysis and animal UTI model. I concluded that the mechanism of action of KPN_2990 can be explained partially by the modulation of proinflammatory cytokines response to Klebsiella infection. Their mode of action is certainly much more complex and further research is necessary for a better understanding of this phenomenon.
論文目次 Contents
Abstract in Chinese I
Abstract III
Acknowledgement V
Contents VII
Table Contents IX
Abbreviations XII
Chapter 1. Introduction 1
1.1 Urinary tract infection and Klebsiella pneumoniae 2
1.2 Diabetes mellitus, liver abscess and Klebsiella pneumoniae 4
1.3 A Population-based cohort survey on the incidence of pyogenic liver abscess in patients with diabetes mellitus 5
1.3.1 Introduction 5
1.3.2 Methods 6
1.3.3 Results 9
1.3.4 Discussion 14
1.4 Thesis aims 19
Chapter 2. The Association Between Diabetes Mellitus and Chronic Kidney Disease from Population Based Study 21
2.1 Backgrounds and aims 21
2.2 Materials and Methods 24
2.3 Results 28
2.4 Discussion 32
2.5 Figures and Tables 39
Chapter 3. The Close Relationship Between Diabetes Mellitus and Clinical Klebsiella pneumoniae in Urinary Tract Infections 50
3.1 Background and Aims 50
3.2 Materials and Methods 53
3.3 Results 60
3.4 Discussion 64
3.5 Figures and Tables 69
Chapter 4. The Close Relationship Between Diabetes Mellitus and Clinical Klebsiella pneumoniae in Peritoneal Dialysis-Related Peritonitis 77
4.1 Background and Aims 77
4.2 Materials and Methods 80
4.3 Results 82
4.4 Discussion 85
4.5 Figures and Tables 88
Chapter 5. Identification and Survey of The Adhesion Gene KPN_2990 in Klebsiella pneumoniae-Related Urinary Tract Infection 92
5.1Background and Aims 92
5.2 Materials and Methods 94
5.3 Results 99
5.4 Discussion 101
5.5 Figures and Tables 105
Chapter 6. General Discussion, Conclusion and Prospects 114
6.1 Discussion for epidemiologic findings 114
6.2 Discussion for experimental findings 115
6.3 Prospects 116

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