前言: 在台灣，末期腎病變及上泌尿道上皮癌發生率在已知報告都相當高，女性比例也較高。我們已經使用國衛院健保資料庫分出洗腎及泌尿道癌症的發生率及盛行率，並推演可能相關疾病及藥物的使用的影響。由於超過99%病人皆不住在已知的南台灣含砷地區，而可能發生原因如止痛藥、含馬兜鈴酸中草藥都值得探討，另外對於一些抗發炎藥物可能具有預防癌症發生的效果，對末期腎病變病人的泌尿道上皮癌的角色也值得探討。另外，在2003年11月衛生署禁止使用五種含馬兜鈴酸藥材，對於泌尿道上皮癌的影響也值得探討。
研究方法與對象:我們使用健保資料庫重大傷病檔1997-2002, 1997-2008及100萬人抽樣檔資料進行研究，進行四種研究設計。首先使用1997-2002年資料，並以台灣人口為對照組計算泌尿道上皮癌族群的泌尿系統癌症的年紀、性別分層標準發生率，接著使用個人的藥物累積來計算末期腎病變病人透析後新發生泌尿上皮癌發生風險。接著使用1997-2008 資料進行第三、四部分，計算40-84歲末期腎病變病人的逐年標準發生率及累積發生率，計算變化的趨勢，最後加入可能造成及預防泌尿上皮癌的因子，作多變數分析。
結果: 使用1997-2002健保資料庫，在58739位末期腎病變病人中找出687位透析後新發生泌尿上皮癌，以台灣人口為對照組，標準發生率在泌尿道癌症是12.9(95% CI:12.0-13.9)。而女性的22.1 (20.1, 24.3)及小於50歲的74.5 (1.8, 41.2)更是不成比例高。另外在分析由320位透析後新發生泌尿上皮癌病人的資料(由38995位末期腎病變病人) ，使用木通或累計馬兜鈴酸1-100mg或更高都會明顯增加泌尿上皮癌，而超過150顆止痛藥也明顯增加風險。
由1997-2008健保資料庫，分析2708位透析後新發生泌尿上皮癌病人的資料(由90477位洗腎病人，40-84歲族群)，女性的上泌尿道泌尿上皮癌標準發生率及累積發生率在2000年後都有減少趨勢，可能與1998年後中草藥使用含馬兜鈴酸的藥才減少有關。
由1997-2008健保資料庫，分析1243位末期腎病變後新發生泌尿上皮癌病人的資料(由98243位洗腎病人)，使用乙醯胺酚或累計馬兜鈴酸在1-100mg或更高都會明顯增加泌尿上皮癌，使用木通也明顯增加膀胱癌風險，但是在超過60g才增加上泌尿道泌尿上皮癌風險。而使用statin類藥物及阿斯匹靈可明顯發現減少泌尿上皮癌風險，但是如果累計馬兜鈴酸劑量超過100mg則無效。
結論: 暴露含馬兜鈴酸中草藥與末期腎病變病患產生泌尿上皮癌有關，在逐年減少使用後，女性洗腎患者的上泌尿道泌尿上皮癌也呈現減少趨勢，除馬兜鈴酸外，乙醯胺酚也是一個可能的相關致病因子，另一方面，使用statin類藥物及阿斯匹靈可明顯發現減少泌尿上皮癌風險，但是如果累計馬兜鈴酸劑量超過100mg則無效。所以，雖然已經減少使用含馬兜鈴酸成分的中草藥，但是末期腎病變病人的泌尿上皮癌風險至2008底仍處於高點。在我們這一代，馬兜鈴酸對於公共衛生的影響無庸置疑。雖然對於致病因子及保護因子的進一步了解令人鼓舞，但是實際對國人健康的增進仍有距離，制定有效的管制方法有其急迫性。

Background and Purpose: Both end-stage renal disease (ESRD) and upper tract urothelial cancer (UTUC) bear high incidence rates in Taiwan. Female is also observed higher in development of urinary tract cancer (UTC). We can use National Health Research Institute database (NHRID) to calculate incidence and prevalence rate, and to deduce possible caution and prevention factor, including relation disease and consumption of medicine. Arsenic is a potential confounder although more than 99% of UC cases resided in area out of 4 traditional endemic areas of arsenic in Southwest Taiwan. Other possible predisposing factors include analgesics, aristolochic acid (AA) containing Chinese herbal products (CHP). Some anti-inflammation agents are also potential chemoprevention for occurrence of UC in chronic dialysis patient. Otherwise, in Nov 2003 prohibition of 5 herbal components containing AA was promulgated by the Department of Health. This policy may have impact on development of UC.
Methods: We used NHIRD 1997-2002, 1997-2008 and 1,000,000 randomized samples as our study database. There are four designs to answer different questions. First, we used 1997-2002 NHIRD data to calculate standardized incidence ratios (SIRs) of urinary tract cancer among ESRD and general population as reference. Second, cox-regression model to calculate hazard ratios of UC in ESRD with factors of AA-CHP, analgesics and acetaminophen from NHIRD claims. Third, using 1997-2008 NHIRD, we calculated 40-84 y/o cumulative incidence rate (CIR40-84) and SIR40-84 and tested trend by calendar year. Fourth, using 1997-2008 NHIRD we put potential caution and prevention agents on UC among ESRD.
Results: Using 1997-2002 NHIRD, there are 687 new developed UTC among 58,739 patients with ESRD. Using the general population as the reference group, SIRs were 12.9 (95% CI (confidence interval): 12.0-13.9) for all UTC cases. SIRs are disproportionate high in female of 22.1 (95% CI: 20.1, 24.3) and younger, namely, less than 50 y/o of 74.5 (95% CI: 1.8, 41.2). Another similar period study sorting 320 patients developed UC after ESRD from 38,995 ESRD patients. Having been prescribed Mu Tong or an estimated consumption of aristolochic acid (esAA) more than 1-100 mg, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC.
Another study sorting 2,708 new developed UC from 90,477 ESRD between1997 and 2008 covering the patients aged 40-85. The time trends of CIR40-84 and SIR40-84 of UTUC in females appear to decline after calendar year 2000. These trends may be related to AA-associated herbal products after 1998.
Moreover, during 1998-2008 data, 1,243 new developed UC were sorted from 98,243 ESRD patients. Having been prescribed of esAA and acetaminophen increased risk significantly for UC. Significantly increased risk of lower tract UC if Mu Tong ever been prescribed, and at upper tract UC became significant at consumption more than 60 g. At chemoprevention agents, significant reduced hazard of UC in cases having been prescribed statin and aspirin in cases without exposure or less than esAA of 100 mg. More than 100 mg consumption the benefit will become marginal.
Conclusions: Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. After decline in prescription of AA-CHP during study period, we found a similar trend in female UTUC incidence. The time trends associate with the consumption of aristolochic acid. Exception to AA-CHP consumption, acetaminophen is also a potential causal factor. Promising chemopreventive effect is found at aspirin and statin usage, but more than 100 mg AA consumption this effect is not promising. In conclusion, although AA-CHP consumption is decreasing, hazard of UC in ESRD patients was still high in end of 2008. Consumption of aristolochic acid herbal products implicitly impact public health in this generation. Although more understanding of causal and prevention factors are encouraging, developing practically regulations are indeed urgent.

誌謝 …………i
中文摘要 …………ii
英文摘要 …………iv
目錄 …………vii
附錄 …………viii
表目錄 …………x
圖目錄 …………xi
論文內文

Chapter 1 ……………1
Background and Paper Reviews
1.1 Background
1.2 Epidemiological evidence about high upper tract urothelial cancer percentage: even more severe in end stage renal disease
1.3 Uremia and patient underwent kidney transplant in Taiwan presented high incidence rate in upper tract urothelial cancer
1.4 Why study of UTUC is important in patients with chronic kidney disease and renal replacement therapy
1.5 Possible pathogenesis and evidence for UTUC
1.6 The role of Aristolochic acid in Taiwanx
1.7 The role of Arsenic in Taiwan
Chapter 2 ……………15
Specific Aims, research design and methods
Chapter 3 ……………18
Epidermiolgical study of urinary tract cancer in ESRD
3.1 Introduction
3.2 Material and methods
3.3 Results
3.4 Discussion
3.5 Conclusions
Chapter 4 ……………33
Increased Upper and Lower Tract Urothelial Carcinoma In Patients
With End Stage Renal Disease: A Nationwide Cohort Study in Taiwan During
1997-2008
4.1 Introduction
4.2 Material and methods
4.3 Results
4.4 Discussion
4.5 Conclusions
Chapter 5 ……………49
Increased risk of urinary tract cancer in ESRD patients associated with usage of Chinese herbal products suspected of containing aristolochic acid
5.1 Introduction
5.2 Material and methods
5.3 Results
5.4 Discussion
5.5 Conclusions
5.6 Appendix
Chapter 6 ……………71
Statins and aspirin associate with reduced risk of aristolochic acid
related urothelial carcinoma in end-stage renal disease
6.1 Introduction
6.2 Material and methods
6.3 Results
6.4 Discussion
6.5 Conclusions
參考文獻 ……………100
Supplementary Table and Figure ……………113
附錄
Appendix 1 ……………115

Shuo-Meng Wang, Ming-Nan Lai, Pau-Chung Chen, Jung-Der Wang. Increased risk of urothelial cancer in young and middle aged patients with end-stage renal disease
Journal of the Formosan Medical Association. Published online: December 20, 2013

Appendix 2 ……………116
Shuo-MengWang, Ming-Nan Lai, Pau-Chung Chen, Yeong-Shiau Pu, Ming-Kuen Lai,Jing-Shiang Hwang, and Jung-DerWang. Increased Upper and Lower Tract Urothelial Carcinoma in Patients with End-Stage Renal Disease: A Nationwide Cohort Study in Taiwan during 1997–2008.
BioMed Research International Received 23 February 2014; Accepted 15 May 2014; Published 16 June 2014

Appendix 3 ……………117
Shuo-Meng Wang, Ming-Nan Lai, Alan Wei, Ya-Yin Chen,Yeong-Shiau Pu, Pau-Chung Chen, Jung-Der Wang
Increased risk of urinary tract cancer in ESRD patients associated with usage of Chinese
herbal products suspected of containing aristolochic acid
(PLOS ONE, minor revision,2014/4/25)

Appendix 4 ……………118
Statins and aspirin associate with reduced risk of aristolochic acid related urothelialcarcinoma in end-stage renal disease (preparation)
&;#8195;
List of Figures
Figure 3.1 …………… 42
Flowchart of recruitment of urinary tract cancer cases from reimbursement data of NHIRD 1997-2002.
Figure 3.2 ……………43
Incidence rates of urinary tract cancer in patients with ESRD (end stage renal disease) and general population of Taiwan.
Figure 4.1 ……………55
Flowchart of recruitment of subjects in this study.
Figure 4.2 ……………56
Calendar-time trends of prevalence of smoking in general population and prescription frequencies of aristolochic acid (A.A.)-related and Xi-Xin Chinese herbal products (CHPs) in 90,477 patients with ESRD (end-stage renal disease), stratified by sex.
Figure 4.3 ……………57
Estimated trend coefficients with 95% confidence intervals for SIR (standardized incidence ratio). Abbreviations: LTUC, lower urinary tract urothelial cancer; UTUC, upper tract urinary tract urothelial cancer; ESRD, end stage renal disease.
Figure 5.1 ……………82
Correlation analysis between prescription of analgesics (number of pills) and cumulative dose of aristolochic acid for both cases and controls.&;#8195;
List of Tables
Table 3.1 ……………44
Distribution of cancers of the urinary tract, bladder, kidney, ureter and pelvis in patients with end-stage renal disease in Taiwan.
Table 4.1 ……………58
Characteristics of patients with end-stage renal disease between 40-84 years-old under maintenance dialysis in the registry of catastrophic illnesses between Mar.1997 and Dec.2008.
Table 4.2 ……………59
Age- standardized incidence rates (aged between 40 and 84) for patients under maintenance dialysis stratified by sex and calendar year.
Table 4.3 ……………60
Sex- and age-specific rates (per 100,000 person-years) and cumulative incidence rates up to 84 year-old (CIR40-84) of urothelial cancer calculated for every 3-year interval between 1997 and 2008.
Table 5.1 ……………78
Frequency distributions of various risk factors for the occurrence of urinary tract cancers (UTC) stratified by different inclusion criteria in 38,995 patients with end-stage renal disease (ESRD).
Table 5.2 ……………80
Crude and adjusted hazards ratios (HR), and 95% confidence intervals (CI) estimated from multivariate Cox regression models for urinary tract cancer developed in patients with ESRD.
Table 6.1 ……………99
Demonstration of patients recruited between 1997-2008.
Table 6.2 ……………102
Divided urothelial cancer into upper tract and low tract. Cox-regression model to demonstrate hazards of development UC with potential factors.
Table 6.3 ……………104
Cox-regression model to demonstrate hazards of development UC with potential factors. Aristolochic acid is demonstrated as estimated accumulation dose of aristolochic acid.
Table 6.4 ……………106
Divided cases into different exposure groups of estimated aristolochic acid of 0, 1-100 and more than 100mg. Abbreviations: LTUC, lower urinary tract urothelial cancer; UTUC, upper tract urinary tract urothelial cancer.
Table 6.5 ……………109
Cox-regression model to demonstrate hazards of development UC with potential factors.
Table 6.6 ……………111
Divided cases into upper and lower tract urothelial cancer with different exposure of estimated aristolochic acid exposure. Hazards ratios of urothelial cancer is presented at different exposure of statin and aspirin.

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