研究背景：比利時的馬兜鈴酸腎病變後，全球世界各地，陸續發生類似之中藥腎病變，及導致之泌尿上皮腎臟癌、輸尿管癌及膀胱癌，加上實驗室的研究，更加確認馬兜鈴酸腎病變及致癌性，許多先進國家因對中藥安全疑慮而採取管制措施，間接影響國內中草藥產業的發展與外銷。近年來國內洗腎及泌尿道癌人口的增加造成人民傷痛及健保負擔沉重，混誤用馬兜鈴酸中藥(防己為廣防己混誤用；木通為關木通混誤用；木香為青木香混誤用)是否扮演一部份角色，也需探討。所以本研究目標為針對過去混誤用馬兜鈴酸中藥處方(單味藥及複方) 在控制可疑腎毒性西藥之變因下進行探討，以分析上述藥是否會導致慢性腎病及泌尿道癌。以期建立「中草藥安全性」使用環境及確立「馬兜鈴酸危險濃度」，逐步建立國內國際中草藥產業更安全的把關機制。
材料與方法：本研究的設計首先是利用健保20萬抽樣歸人檔資料計算過去1997至2002年在醫師處方模式下的中藥及西藥使用的狀況，採用回溯性的世代追蹤研究法分析研究標的中藥方劑(即含細辛、馬兜鈴、天仙藤、防己、木通、木香中藥或方劑之濃縮中藥)及腎毒性西藥（非類固醇消炎藥(NSAIDs)、及止痛藥acetaminophen）的情形，並同時考慮年齡、性別、糖尿病及高血壓等變數，以慢性腎病發生為結果，進行世代分層分析統計，並使用Cox proportional hazards model 來加以控制變因，分析這些決定因子的相對風險（Hazards ratio），並探討藥物劑量與疾病發生之相關。
然後再利用健保20萬抽樣歸人檔資料及重大傷病名單，連結全國所有洗腎患者及腎泌尿道癌患者名單的門診及住院醫療明細檔，採用個案對照研究法，分析過去1997至2002年洗腎患者及泌尿道癌患者於罹病前在醫師處方模式下的中西藥使用的狀況，包括研究標的中藥方劑(即含細辛、馬兜鈴、天仙藤、防己、木通、木香中藥或方劑之濃縮中藥)及腎毒性西藥（非類固醇消炎藥(NSAIDs)、及止痛藥acetaminophen）的情形。並且用分層分析，納入年齡、性別、糖尿病、高血壓、居住地（烏腳病流行區）及使用上述中藥疾病等變項，再使用多變數羅吉式迴歸（multi-variant logistic regression）來分析這些決定因子的勝算比，並探討藥物劑量與疾病發生之相關。
結果：根據1997-2002年這份20萬抽樣歸人檔資料，有112,264人（佔56.2％）看過中醫門診。在此期間(1997年8月至2002年12月31日) 共有2343新的慢性腎病患者，男性1208人（佔51.6％），女性1135人（佔48.4％），平均年齡 59.3 ± 17.0歲。慢性腎病平均發生率為百萬人年分之1,964。著依據上述分層原則進行Cox回歸模型(regression model)計算出發生慢性腎病風險比（HR，hazards ratio）， 發現處方超過 30克(關)木通，或超過60克(廣)防己、會統計上有意義的增加慢性腎病風險比(統計上有意義， p < 0.05)。小於50歲女性會增加慢性腎病風險比。發現肌肉骨骼疾病、泌尿道疾病、腸胃道疾病、神經疾病、及心理疾病在慢性腎病族群比無慢性腎病族群較為常見。
根據1997-2002年這份全國洗腎病人資料，共有58121洗腎病人。在1998年1月至2002年12月31日，共有36,620新的末期腎病患者，粗發生率和世界人口標準化發生率分別為百萬分之329 和323。90歲以下累積發生率是0.056。
在扣除原有慢性腎病案例10777人(1997年7月以前)，共有25843人進入最後的分析個案組。對照組由20萬抽樣歸人檔名單扣除洗腎患者或慢性腎病患者15067人及資料不完全者82人，則有184,851人。本研究使用多變數羅吉式迴歸（multi-variable logistic regression）並用頃向分析(propensity score)來加以調整後的勝算比。(關)木通大於60克及(廣)防己大於60克都有較高的勝算比(關木通 1.47-5.82; 廣防己1.60-1.94），並且呈現劑量反應關係。而高劑量的天仙藤、木香、馬兜鈴、細辛都沒有統計有意義的勝算比增加。
根據1997-2002年這份全國泌尿道癌病人資料，共有20777泌尿道癌病人。在2001年1月至2002年12月31日，共有5995新的泌尿道癌患者，為個案組，粗發生率為百萬分之105。
若進一步扣除被處方非類固醇消炎藥（NSAIDs）及acetaminophen加總大於500顆的族群，剩下個案組4594人及對照組174,701人。在邏輯回歸模型一，男性（勝算比= 1.7，95％信賴區間為 1.6〜1.8），年齡，居住在烏腳病流行鄉鎮（勝算比= 4.4，95％信賴區間為 3.4〜5.8），具有慢性泌尿道感染病史（勝算比= 1.6，95％信賴區間為 1.3至2.1），及超過 60克(關)木通（61至100克，勝算比為 1.6，95％信賴區間為 1.3至2.1;101-200克，勝算比為2.0，95％信賴區間為 1.4至2.7;> 200克，勝算比為2.1，95％信賴區間為 1.3至3.4）是與泌尿道癌發生風險增加相關的獨立因素。在邏輯回歸模型二，調整所有其他危險因素後，發現劑量超過 150毫克馬兜鈴酸（ 151-250毫克，勝算比為 1.4，95％信賴區間為 1.1至1.8； 251-500毫克，勝算比為 1.6，95％信賴區間為 1.2至2.1;> 500毫克，勝算比為 2.0，95％信賴區間為1.4至2.9）是與泌尿道癌發生風險增加相關的獨立因素。對於發生泌尿道癌的風險，關木通劑量及估計劑量都呈現統計學有意義（P <.001）的線性劑量反應關係。而且含馬兜鈴酸中葯與居住烏腳病流行區沒有顯著的相互作用且是完全獨立的。而高劑量的天仙藤、木香、馬兜鈴、細辛都沒有統計有意義的勝算比增加。。
結論與建議：本研究利用1997-2002年期間健保資料，中藥的使用在台灣是非常普遍，6年約有56％的居民使用健保服用中藥。因為在2003年11月禁止含有馬兜鈴酸中藥(關木通和廣防己)前，木通和防己分別被關木通和廣防己混誤用，導致本研究發現，那時期的木通和防己處方會引起腎病及泌尿道癌。禁止後，我們也建議普遍監視中草藥產品是否含有馬兜鈴酸以預防馬兜鈴酸腎病。
本研究發現超過 30克關木通，或超過60克廣防己，會增加慢性腎病風險比；超過 60克關木通或廣防己，增加末期腎病風險；超過 60克關木通或超過 150毫克馬兜鈴酸中藥產品，增加泌尿道癌發生風險；並且有線性劑量反應關係。我們也建議普遍監視有馬兜鈴酸腎病病人或禁止馬兜鈴酸中藥前有服用木通或防己(即使是少劑量)的族群，應定期監測是否有泌尿系統腫瘤。
本研究提供馬兜鈴酸中藥導致慢性腎病、末期腎病及泌尿道癌的臨界劑量，這對建立中草藥或食物中含有微量馬兜鈴酸的管制是有幫忙的，尤其本研究皆發現馬兜鈴酸含量極微的細辛皆無增加慢性腎病、末期腎病或泌尿道癌發生風險，現階段應無禁止細辛之必要，也可因此向國外中藥市場爭取細辛解禁，但應持續觀察長期服用細辛10年以上病人是否有腎病風險。
本研究也顯示，「不同的中藥混合，以抵消其毒性」的傳統中醫藥理論似乎在馬兜鈴酸中藥是不支持的，政府除了繼續維持GMP中藥廠控管品質，也應該時常管制抽檢民間中藥或不明來源藥物或健康食物是否含有馬兜鈴酸，以確保全民的健康。

Background：Nephropathy or urinary tract cancer.associated with aristolochic acid (AA) has been documented by human and animal studies. Taiwan has a remarkably high incidence of end-stage renal disease (ESRD).
Aims: The objective of this study intends to determine the risks of chronic kidney disease (CKD), end stage renal disease (ESRD) or urinary tract cancer associated with Chinese herbal products (CHP) highly suspected to contain AA (Ma-Dou-Ling, Tian-Xian-Teng, Xi-Xin, (Guan-)Mu-Tong, (Guang-)Fangchi, and Mu-Xiang) through a population-based database of the National Health Insurance (NHI) system of Taiwan.
There are 3 studies as follows:
1. Risks of chronic kidney disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid
Materials and Methods: A retrospective follow-up study was conducted, using a simple random sample (200 000 people) in the National Health Insurance reimbursement database during 1997–2002. Cox regression models were constructed to control potential confounders, including age, sex, hypertension, diabetes mellitus, and use of non-steroidal anti-inflammatory drugs and acetaminophen.
Results: A total of 199 843 persons were included in the final analysis, 102 464 (51.3%) men and 97 379 (48.7%) women, with an average incidence rate of 1964/106 person-years for CKD and 279/106 person-years for ESRD. After controlling other risk factors, the hazard ratios for development of CKD seemed to increase for patients that had consumed more than 30 g Mu-Tong, and more than 60 g Fangchi.
Conclusion: Prescription of more than 30 g Mu-Tong or more than 60 g Fangchi CHP was associated with an increased risk of developing CKD. In addition to prohibiting the use of Guan-Mu-Tong and Guang-Fangchi, patients who have used these CHP should continue to be followed up.
2. Risks of end-stage renal disease associated with prescribed Chinese herbal products suspected to contain aristolochic acid
Materials and Methods: The registries for patients with end stage renal disease (ESRD) in the reimbursement database of catastrophic illnesses from NHI (National Health Insurance) in Taiwan during 1997 – 2002 were collected as the cases, while a simple random sample of 200,000 people would be used as controls after excluding patients with kidney diseases. Potential risk factors, including age; sex; hypertension; diabetes; cumulative doses of nonsteroidal anti-inflammatory drugs, acetaminophen, and adulterated herbal supplements potentially containing aristolochic acid before the development of chronic kidney disease; and indications for prescribing such herbs, including chronic hepatitis, chronic urinary tract infection, chronic neuralgia, or chronic musculoskeletal diseases, were assessed for independent association with occurrences of end-stage renal disease through construction of multiple logistic regression models.
Results: There were 36,620 new ESRD cases from 1998 through 2002. After exclusion of cases with chronic kidney disease diagnosed before July 1, 1997, there were 25,843 new cases of ESRD and 184,851 controls in the final analysis. After adjustment for known risk factors, cumulative doses > 60 g of Mu Tong (OR, 1.47 [95% CI, 1.01-2.14] for 61-100 g; OR, 5.82 [95% CI, 3.89-8.71] for > 200 g) or Fangchi (OR, 1.60 [95% CI, 1.20-2.14] for 61-100 g; OR, 1.94 [95% CI, 1.29-2.92] for > 200 g) were associated with increased risk of the development of ESRD with a dose-response relationship.
Conclusions: Consumption of > 60 g of Mu Tong or Fangchi from herbal supplements was associated with an increased risk of developing kidney failure (ESRD).
3. Risks of urinary tract cancer associated with prescribed Chinese herbal products suspected to contain aristolochic acid
Materials and Methods: All patients newly diagnosed with urinary tract cancer (case subjects) from 2001 to 2002, and a random sample of the entire insured population from 1997 to 2002 (control subjects), were selected from the National Health Insurance reimbursement database. Subjects who were ever prescribed more than 500 pills of nonsteroidal anti-inflammatory drugs and/or acetaminophen were excluded, leaving 4594 case patients and 174 701 control subjects in the final analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multivariable logistic regression models for the association between prescribed Chinese herbs containing aristolochic acid and the occurrence of urinary tract cancer. Models were adjusted for age, sex, residence in a township where black foot disease was endemic (an indicator of chronic arsenic exposure from drinking water [a risk factor for urinary tract cancer]), and history of chronic urinary tract infection. Statistical tests were two-sided.
Results: Having been prescribed more than 60 g of Mu Tong and an estimated consumption of more than 150 mg of aristolochic acid were independently associated with an increased risk for urinary tract cancer in multivariable analyses (Mu Tong: at 61–100 g, OR = 1.6, 95% CI = 1.3 to 2.1, and at >200 g, OR = 2.1, 95% CI =1.3 to 3.4; aristolochic acid: at 151–250 mg, OR = 1.4, 95% CI = 1.1 to 1.8, and at >500 mg, OR = 2.0, 95% CI = 1.4 to 2.9), with a statistically significant linear dose–response relationship.
Conclusions: Consumption of aristolochic acid–containing Chinese herbal products is associated with an increased risk of cancer of the urinary tract in a dose-dependent manner that is independent of arsenic exposure.

口試委員會審定書…………………………………………………. i
誌謝…………………………………………………………………. v
中文摘要……………………………………………………………. vi
英文摘要……………………………………………………………. ix
第一章 研究背景…………………………………………………. 1
第一節 前言…………………………………………………… 1
第二節 馬兜鈴酸腎病的文獻回顧…………………………… 3
第三節 傳統中草藥和馬兜鈴酸中草藥安全研究的必要性… 11
第二章 材料與方法…………………………………………….… 14
第一節 混誤用馬兜鈴酸中藥處方與慢性腎病之發生……… 14
第二節 混誤用馬兜鈴酸中藥處方與末期腎病之發生……… 19
第三節 混誤用馬兜鈴酸中藥處方與泌尿道癌之發生……… 24
第三章 結果…………………………………………….…………. 29
第一節 混誤用馬兜鈴酸中藥處方與慢性腎病之發生……… 29
第二節 混誤用馬兜鈴酸中藥處方與末期腎病之發生……… 32
第三節 混誤用馬兜鈴酸中藥處方與泌尿道癌之發生……… 34
第四章 討論…………………………………………….…………. 36
第一節 混誤用馬兜鈴酸中藥處方與慢性腎病之發生………. 36
第二節 混誤用馬兜鈴酸中藥處方與末期腎病之發生………. 40
第三節 混誤用馬兜鈴酸中藥處方與泌尿道癌之發生………. 44
第五章 結論與建議……………………………………….……….. 47
參考文獻……………………………………………………………... 48
附錄…………………………………………………………………... 84
附件一、已被國外期刊接受刊登論文(慢性腎病) …………… 84
附件二、已被國外期刊接受刊登論文(末期腎病) ………….. 92
附件三、已被國外期刊接受刊登論文(泌尿道癌) ………….. 104

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