Acute interstitial nephritis

Definition presence of inflammatory infiltrates and edema within the interstitium Acute interstitial nephritis Kidney International (2010) 77, 956–961

Pathogenesis The initial event: expression of endogenous nephritogenic antigens or exogenous antigens processed by tubular cells  Tamm–Horsfall protein  Megalin: a protein localized in the brush border of proximal tubular cells  Components of TBM: tubulointerstitial nephritis antigen

Cell-mediated immunity:  The inflammatory cellular infiltrates that characterize AIN, mainly composed of T lymphocytes and macrophages.  Increase the production of extracellular matrix and the number of interstitial fibroblasts  Induce an amplification process recruiting more inflammatory cells and eosinophils into the interstitium

Profibrotic cytokines and growth factors:  Transforming growth factor-b  Platelet-derived growth factor-BB  Endothelin-1  Epidermal growth factor  Fibroblast growth factor-2

Clinical features In patients with drug-induced AIN, mean delay between the starting of the offending drug and the appearance of renal manifestations is 10 days.

Early steroid treatment improves renal function recovery in patients with drug-induced acute interstitial nephritis Kidney Int 2008; 73: 940–946. Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 2004; 19: 2778–2783

Treatment Conservative treatment:  Larger number of patients and a longer follow- up revealed that a significant proportion of patients, ranging from not fully recovered their baseline renal function.  Duration of treatment with the offending drug or duration and severity of renal failure have not shown a clear correlation with the levels of serum creatinine at the end of follow-up.

Steroid: early use  Intravenous pulses of methylprednisolone (250 mg daily for 3 consecutive days) followed by oral prednisone (0.5–1 mg/kg/day) tapering off over 4–6 weeks Anti-TBM disease: Plasmapheresis and cytotoxics Idiopathic AIN resistant to steroids: cyclophosphamide, cyclosporine, mycophenolate mofetil

Rapidly progressive interstitial fibrosis associated with chinese herbal medicine

Clinical features Glomeruli were apparently intact Nearly normal blood pressure, obvious anemia, insignificant edema, low-grade proteinuria and glucosuria Renal function declined rapidly Rapidly progressive interstitial fibrosis associated with chinese herbal medications Am J Nephrol. (2001) Nov-Dec;21(6):441-8 Rapidly progressive interstitial fibrosis associated with chinese herbal drugs Am J Kidney dis (2000) Feb35(2):313-8

Historical background 1993 年，比利時學者 Vanherweghem 發現 2 名婦女因服含 “ 防己（ Stephania tetrandra ） ” 的減肥藥出現進行性腎損 害，病理組織學表現為腎間質纖維化，從而引發 “ 中草藥 腎病 ” （ Chinese herbs nephropathy ， CHN ）的提出。  防己是常用的利水消腫，祛風止痛藥  粉防己 （漢防己 Stephania tetrandra ）為防己科植物粉防己的 乾燥根，廣防己（木防己 Arislochia fangchi Y.C ）為馬兜鈴科植 物廣防己的乾燥根，還有馬兜鈴科植物異葉馬兜鈴的根亦入藥稱 “ 漢中防己 ”  誤將木防己為漢防己使用所致 。 Vanherweghem 報導至 1998 年在比利時大約有 100 名以上 的 “ 中草藥腎病 ” 患者，其中至少已有 70 名患者接受了透析 或腎移植治療。

Historical background 臺灣、英國、法國、波蘭、加拿大、美國 等地出現了類似的臨床病例報導。  1997 年日本媒體報導，當歸四逆加吳茱萸生薑糖 顆粒劑腎毒害事件  2003 年中國大陸的 “ 龍膽瀉肝丸事件 ”  1999 年英國報導之中草藥腎病，可能由對於木通 缺少正確的藥物鑒定，因疏忽將關木通（馬兜鈴 科纏繞藤本植物木通馬兜鈴 Aristolochia manshuriasis Kom ）當作川木通（毛莨科小木通 Clematic armandii Franch ）使用 。

Historical background 2000 年新英格蘭雜誌， Nortier 對於一組 39 例接受腎移植患者的摘除腎進行研究，發 現在所有的腎組織中，均存在馬兜鈴酸相 關的 DNA 加成物，其中 17 例有輸尿管癌、 腎盂癌或兩者均有， 1 例膀胱癌, 另外 19 例患 者均存在輕到中度的尿路結構不良

馬兜鈴酸的作用 早期的動物實驗顯示馬兜鈴酸能顯著的增強吞噬 細胞的吞噬功能，提高動物抗菌能力和免疫功能； 也有抗癌作用，用於治療各種感染症、皮膚病， 提升腫瘤病人的免疫力和腫瘤病人化學療法後的 白血球減少。但是在人體施行臨床試驗，不見上 述療效。 一九五八年歐美學者已經證明馬兜鈴酸具有腎毒 性，在兔子和鼠類都有傷害腎臟的報告。一九六 四年美國國立癌症中心支持的馬兜鈴酸第一期人 體臨床試驗，發現馬兜鈴酸在人體會造成腎小管 壞死。

含有馬兜鈴酸的中藥 含有或可能含有馬兜鈴酸的常用中藥品種為  馬兜鈴科馬兜鈴屬的中藥材如：關木通、廣防已、青木香、 天仙藤、朱砂蓮、尋骨風、青香藤、南木香、通城虎、假 大薯、淮通、管南香、鼻血雷、白金古欖等  馬兜鈴科細辛屬的中藥材如：細辛、黃細辛、花臉細辛、 召葉細辛、杜衡、金耳環等，都含馬兜鈴酸。 含馬兜鈴酸的常見成藥  龍膽瀉肝丸、耳聾丸、八正丸、純陽正氣丸、大黃清胃丸、 當歸四逆丸、導赤散、甘露消毒丹、排石顆粒、跌打丸、 婦科分清丸、冠心蘇合丸、蘇合丸、辛荑丸、十香返生丸、 濟生桔核丸、止嗽化痰丸等。

“ 馬兜鈴酸腎病 ” （ aristolochic acid nephropathy; AA nephropathy ） 區分其它中草藥腎病 急性腎小管壞死及腎間質纖維化  急性腎衰竭  嚴重的電解質不平衡 泌尿系統移行上皮細胞癌  腎盂癌輸、尿管癌、膀胱癌  無痛血尿 患者臨床表現和病理類型的急慢輕 重與服用藥物的劑量（單劑量、持 續時間）有關。

AA p53 H-ras p53 H-ras AA metabolites: Aristolactams I and II deoxyadenosindeoxyguanosin 泌尿系統移行上皮細胞癌

Mechanisms of AA Nephropathy Pathological features  Similar features as antibiotics-induced acute tubular necrosis: epithelial necrosis, collapse and exofoliation.  Exceptional features: rare cell regeneration and a tendency towards fibrosis  A severe loss of proximal tubular cells (PTCs) and disrupted PTC basement membrane.

TGF-  Kidney Injury Kidney Injury Transforming growth factor-  CTGF Connective tissue growth factor Extracellular matrix protein: type I, III and IV collagen, fibronectin ECM transdifferentiation

The central role of TGF-1 in renal fibrosis TGF-  1 Regulate cytokines CTGF FGF-2 Angiotensin TNF Chemotaxis Lymphocyte Macrophage Activate fibroblast Tubular cell Mesangial cell Matrix Synthesis degradation Hypertrophy Apoptosis Necrosis Proliferation Migration

TGF-  1 CTGF Control Antibiotics-ATN AA-ATN

Control Antibiotics-ATN AA-ATN Type III collagen Type IV collagen

Control Antibiotics-ATN AA-ATN  -SMA fibronectin

Comparison of expression of profibrotic cytokines, myofibroblast marker and extracellular matrix

Possible protective medicine of renal fibrosis Angiotensin II inhibitors Angiotensin receptor antagonists Aldosterone receptor antagonists Statin

Possible protective medicine of renal fibrosis Glycyrrhiza 甘草  Treatment of viral hepatitis and hepatic inflammation  Antiperoxidation and inhibition of liver fibrosis  Irritable skin disease  Prevention of liver cancer

Protective effect of possible drugs in AA Nephropathy 1.Mu-Tong 2. + captopril 3. + losartan 4. + simvastatin 5. + spirolactone 6. + diammonium glyrrhizinate Zhu et al. Am J Nephrol, 2005 Blood BUN Blood Creatinine

1.Mu-Tong 2. + captopril 3. + losartan 4. + simvastatin 5. + spirolactone 6. + diammonium glyrrhizinate Zhu et al. Am J Nephrol, 2005 Blood procollagen III Renal fibrosis area by Masson staining Protective effect of possible drugs in AA Nephropathy

The RAS blockade does not prevent the AA-induced interstitial fibrosis Animal model: Wistar rat Enalpril or enalpril+candesartan No difference in terms of renal failure, proteinuria and interstitial fibrosis at day 35 or 65. Debelle et al. Kidney Int, 2004

Impact of Aristolochia fangchi ingested dose Martinez et al. Nephrol Dial Transplant, 2002

Effects of Steroids on Chinese Herb Nephropathy Study group: 12 patients  1 mg/kg for one month  Tapering 0.1 mg/kg every 2 weeks Control group: 23 patients Vanherweghem et al. Am J Kidney Dis, 1996

Final outcome Steroid group: 2/12 (16.7%) patients on renal replacement therapy at 1 year. Control group: 16/23 (52.2%) patients on renal replacement therapy at 1 year (p<0.005) Vanherweghem et al. Am J Kidney Dis, 1996

Effect of dexfenfluramine on AA nephropathy Dexfenfluramine (DXF): appetite suppressant Chinese-herb nephropathy after concomitant intake of DXF and AA. The formation of AA-DXF adducts in the kidneys

Tubulointerstitial injury score Serum creatinine Effect of dexfenfluramine on AA nephropathy control DXFAADXF+AA

Conclusion Careful utilization of medicine containing aristolochic acid The outcome of AA nephropathy is catastrophic if it is discovered in the advanced stage. Early intervention with steroids might delay requirement of RRT. ARB or ACE inhibitors are recommended although its beneficial effect remains unclear.

衛生署中醫藥委員會禁用含馬兜鈴酸 : 2003/11/03 臺灣衛生署對含有馬兜鈴酸中藥的管理

【資料提供／衛生署中醫藥委員會】 中文 品名 製造廠商 ‧ 馬兜鈴 順天堂馬兜鈴濃縮顆粒順天堂藥廠新店廠 順天堂補肺阿膠散濃縮散順天堂藥廠新店廠 順天堂補肺阿膠散濃縮顆粒順天堂藥廠新店廠 東陽補肺阿膠散濃縮散東陽製藥公司 晉安補肺阿膠散濃縮散晉安製藥公司頭橋廠 港香蘭補肺阿膠散濃縮細粒港香藍藥廠 科達補肺阿膠散濃縮細粒科達製藥公司 正揚補肺阿膠散濃縮散正揚製藥公司 勝昌補肺阿膠散濃縮散勝昌製藥公司 明通補肺阿膠散濃縮細粒明通化學藥廠第二廠 明通補肺阿膠散明通化學藥廠 天良牌保肺抗嗽單散天良 生物科技 高雄廠 生物科技

南和牌鎮嗽散南和化學製藥廠 龍德電咳散龍德製藥廠 人壽止嗽丹人壽製藥廠 保安堂保肺散得力興業化學公司 人壽風寒治嗽散人壽製藥廠 長安芷嗽丹散長安化學工業公司 大昌止嗽散（廠方）大昌製藥廠 大昌牌克嗽散（止嗽散加減味）大昌製藥廠 龍虎堂咳嗽丹龍虎堂醫藥公司 勝利治嗽散勝利製藥廠 鐵牛滅嗽散養生製藥廠 龍虎堂治嗽散龍虎堂醫藥廠

人參治嗽糖衣丸金世界製藥廠 人參治嗽丸（衛署成製字第 號） 大世界製藥廠 人參治嗽丸（衛署成製字第 號） 大世界製藥廠 和春清肺止嗽散和春製藥廠 補肺阿膠散大田製藥廠西藥部 萬國補肺阿膠散萬國製藥廠仁德廠 萬國克嗽散萬國製藥廠仁德廠 萬國人參治嗽丸萬國製藥廠仁德廠 萬國人參嗽治丸（大丸）萬國製藥廠仁德廠

萬能牌運功散萬能化學製藥公司 信效滋肺丹散信效藥廠 京華蜜煉川貝枇杷膏黃萬壽化學製藥公司 人參治嗽糖衣丸神農製藥廠 ‧ 天仙藤 順天堂天仙藤濃縮顆粒順天堂藥廠新店廠 福安胃腸藥散福安製藥廠

‧ 青木安 正和歸脾散金生製藥公司 老漢歸脾散正和製藥公司 正揚歸脾散正揚製藥公司 王品歸脾丸王品製藥廠 立安歸脾散立安製藥公司 久德歸脾散久德製藥廠 萬國歸脾散萬國製藥廠仁德廠 陳李濟養心寧神丸（歸脾丸）洽興貿易公司