Cop+Ed+fisse 2006 123Archivio Italiano di Urologia e Andrologia 2022; 94, 1 LETTER TO EDITOR No conflict of interest declared. KEY WORDS: Aristolochic; TCC; Herbal; Balkan nephropathy. Submitted 3 January 2022; Accepted 19 January 2022 To the Editor, Aristolochic acid is one of major causes for upper tract urothelial carcinoma, especially in younger population. While it is mentioned as a cause in guidelines, little is actually known about the toxin by urologists. We are aiming in our letter to provide some direct and clear information to ourselves that would help us to know more about that toxin and how it can adversely affect our patients. What is Aristolochic acid? Aristolochic acid is an acid obtained from a plant that grows in several areas of the world. Its use was started in China as an herbal medicine that was used to treat many diseases, then was advanced to be used in many herbal medications sold over the shelf worldwide (1). Why people use that herbal drug? This herbal supplement was long used as a miracle supplement for weight loss. Other less common uses were arthritis and menstrual problems (1). In Balkan areas; that herb was mixed with wheat used for home baked bread. Importance to urologists Aristolochic acid were found to be significantly associated with interstitial nephritis, end stage renal disease. This is cur- rently known as a major cause of Balkan nephropathy (2). This was also proved to be a carcinogenic causing upper uri- nary tract urothelial carcinoma (3). A recent study (2017) looked for the oncological outcomes of patients with upper tract urothelial carcinoma exposed to Aristolochic acid. This was found to be significantly associated with higher rate of local and contralateral upper tract recurrence, as well as higher rate for intravesical recurrence (4). A recent meta-analy- sis and systematic review (2021) confirmed the same findings of higher rate of intravesical and contralateral recurrence for patients exposed to Aristolochic acid, as well as worse overall and disease specific survival (5). Authorities’ action and obstacles The toxic and carcinogenic effect of Aristolochic acid was raising concerns since 1999. Food and drug administration (FDA) released warning in 2001 about the use of that herbal supplement and started to recall products from the market con- taining the acid. This was followed in 2004 by a warning from health Canada regarding the use of the supplement with an alert to the Canadian border to prevent importing the drug in any form (6, 7). Why Aristolochic acid is a concern 20 years following authorities’ action? The concerns for Aristolochic acid are still existent for three important reasons. First; unlike other known factors as smok- ing, studies did show that patients that stopped the use of Aristolochic acid for more than 5 years were still at the same risk and worse oncological outcomes for upper tract urothelial carcinoma, similar to patients with recent exposure. It seems that exposure produces a permanent genetic alteration that keeps risking the patients’ cancer development despite of cessation of exposure (4). The second problem is the natural growth of the plant in many areas of the world. While the plant may be avoided because of the known risks, studies have confirmed that the toxins of the plant can spread through the soil and affect other vegetables and fruits that can become contaminated by the toxins. That soil contamina- tion leaching into rivers raised some concerns about water contamination in endemic areas where just drinking water may be imposing a risk for Aristolochic acid exposure. Another natural risk is through butterflies that can act as an interme- diate host for the herbal contamination (8, 9). Chan et al. could recently (2016) identify Aristolochic acid in corn, wheat grains and soil samples taken from Balkan areas (10). More recent studies confirmed the same findings as the root veg- etables in Balkan areas were found to be extensively contaminated with Aristolochic acid (11, 12). The last risk is through Aristolochic acid: What urologists should know Mohanarangam Thangavelu, Asmaa Ismail, Ahmed Zakaria, Hazem Elmansy, Walid Shahrour, Owen Prowse, Ahmed Kotb Northern Ontario School of Medicine, Thunder Bay, Ontario, Canada. DOI: 10.4081/aiua.2022.1.123 Archivio Italiano di Urologia e Andrologia 2022; 94, 1 Mohanarangam Thangavelu, Asmaa Ismail, Ahmed Zakaria, et al. 124 Table 1. Plants containing Aristolochic acid (From FDA 2020). Plant name Aristolochia spp. Aristolochia acuminata Lam. Syn. Aristolochia tagalaChamp. Aristolochia argentina Griseb. Aristolochia baetica Linn. Syn. Aristolochia bracteolataLam. Aristolochia bracteata Retz. Aristolochia chilensis Bridges in Lindl. Aristolochia cinnabarina C.Y. Cheng & J.L. Wu Aristolochia clematitis L. Aristolochia contorta Bunge Aristolochia cymbifera Mart. & Zucc. Aristolochia debilis Siebold & Zucc. Syn. Aristolochia longa Thunb. Syn. Aristolochia recurvilabraHance Syn. Aristolochia sinarumLindl. Aristolochia elegans Mast. Syn. Aristolochia hasslerianaChodat Aristolochia esperanzaeKuntze Aristolochia fangchi Y.C. Wu ex L.D. Chow & S.M. Hwang Aristolochia fimbriata Cham. Aristolochia indica L. Aristolochia kaempferi Willd. Syn. Aristolochia chrysops(Stapf) E.H. Wilson ex Rehder Syn. Aristolochia feddei H. Lév. Syn. Aristolochia heterophyllaHemsl. Syn. Aristolochia mollis Dunn Syn. Aristolochia setchuenensisFranch. Syn. Aristolochia shimadaiHayata Syn. Aristolochia thibeticaFranch. Syn. Isotrema chrysops Stapf Syn. Isotrema heterophylla(Hemsl.) Stapf Syn. Isotrema lasiops Stapf Aristolochia kwangsiensisChun & F.C. How Syn. Aristolochia austroszechuanica C. B. Chien & C. Y. Cheng Aristolochia macrophylla Lam. Syn. Aristolochia sipho L'Hér. Aristolochia manshuriensisKom. Syn. Hocquartia manshuriensis(Kom.) Nakai Syn. Isotrema manshuriensis(Kom.) H. Huber Common/alternative name Aristolochia Guan Mu Tong Guang Mu Tong Oval leaf Dutchman's pipe Ukulwe Birthwort Ma Dou Ling Tian Xian Teng Mil homens Ma Dou Ling Tian Xian Teng Qing Mu Xiang Sei-mokkou (Japanese) Birthwort Long birthwort Guang Fang Ji Fang Ji Mokuboi (Japanese) Kwangbanggi (Korean) Fang Chi Kou-boui (Japanese) Indian birthwort Yellowmouth Dutchman's pipe Dutchman's pipe Manchurian birthwort Manchurian Dutchman's pipe Guang Mu Tong Kan-Mokutsu (Japanese) Mokuboi (Japanese) Kwangbanggi (Korean) Plant name Aristolochia maurorum L. ristolochia mollissima Hance Aristolochia pistolochia L. Aristolochia rigida Duch. Aristolochia rotunda Linn. Aristolochia serpentaria L. Syn. Aristolochia serpentariavar. hastata (Nutt.) Duch. Aristolochia serpentaria L. Syn. Aristolochia serpentariavar. hastata (Nutt.) Duch. Aristolochia watsoni Wooton & Standley or Aristolochia watsonii Wooton & Standley Syn. Aristolochia porphyrophylla Pfeifer Aristolochia westlandii Hemsl. or Aristolochia westlandi Hemsl. Aristolochia zollingerianaMiq. Syn. Aristolochia kankauensisSasaki Syn. Aristolochia roxburghianasubsp. kankauensis (Sasaki) Kitam. Syn. Hocquartia kankauensis(Sasaki) Nakai ex Masam. Syn. Aristolochia tagala var. kankauensis (Sasaki) T. Yamaz. Asarum canadense Linn. Syn. Asarum acuminatum(Ashe) E.P. Bicknell Syn. Asarum ambiguum (E.P. Bicknell) Daniels Syn. Asarum canadense var. ambiguum (E.P. Bicknell) Farw. Syn. Asarum canadense var.reflexum (E.P. Bicknell) B.L. Rob. Syn. Asarum furcatum Raf. Syn. Asarum medium Raf. Syn. Asarum parvifolium Raf. Syn. Asarum reflexum E.P. Bicknell Syn. Asarum rubrocinctumPeattie Asarum canadense Linn. Syn. Asarum acuminatum(Ashe) E.P. Bicknell Syn. Asarum ambiguum (E.P. Bicknell) Daniels Syn. Asarum canadense var. ambiguum (E.P. Bicknell) Farw. Syn. Asarum canadense var.reflexum (E.P. Bicknell) B.L. Rob. Syn. Asarum furcatum Raf. Syn. Asarum medium Raf. Syn. Asarum parvifolium Raf. Syn. Asarum reflexum E.P. Bicknell Syn. Asarum rubrocinctumPeattie Asarum himalaicum Hook. f. & Thomson ex Klotzsch or Asarum himalaycum Hook. f. & Thomson ex Klotzsch Asarum splendens (F. Maek.) C.Y. Cheng & C.S. Yang Bragantia wallichii R.Br. Specimen exists at New York Botanical Gardens. Tropicos does not list this species as a synonym for any Thotteaspecies. Kew Gardens Herbarium does not recognize the genera Bragantia. Until additional information is obtained the name used is as cited in J. Nat. Products 45:657–666 (1982) Common/alternative name Virginia snakeroot Serpentaria Virginia serpentary Virginia snakeroot Serpentaria Virginia serpentary Wild ginger Indian ginger Canada snakeroot False coltsfoot Colic root Heart snakeroot Vermont snakeroot Southern snakeroot Wild ginger Indian ginger Canada snakeroot False coltsfoot Colic root Heart snakeroot Vermont snakeroot Southern snakeroot Tanyou-saishin (Japanese) Do-saishin (Japanese) currently existing other herbal supplements widely used worldwide. While the intentional inclusion of Aristolochic acid is currently not allowed, contamination of the available herbal supplement with Aristolochic acid is a continuous risk. Abdullah et al. (2017) examined 573 different samples lacking Aristolochic acid as one of the ingredients. They could identify the substance in 206 samples (36%). This was a surprising fact that 1/3 of herbal supplements in market could be contaminated with Aristolochic acid (13). What are the herbs that can possibly contain Aristolochic acid? There were many plants reported in a monograph published in 2018 that can possibly contain Aristolochic acid. Most of these herbs have common names that are far away from the original toxin name including Dutchman’s pipe, Virginia snakeroot, Canada snakeroot, wild ginger and Indian ginger (14). More recently, FDA updated its plant lists providing warning to the manufacturers and the public against the use of large numbers of herbs that can potentially harbour the toxin (15). Table 1 illustrate the plants having the toxin. 125Archivio Italiano di Urologia e Andrologia 2022; 94, 1 Aristolochic acid Are there ongoing ways for population protection against the toxin exposure? Herbal medicine is being used worldwide as an alternative medicine that can augment the traditional medicine. The main issues are the large number of plants that can be harbouring the toxin together with possible language barriers and the use of English names to some herbs that can be completely different and not presenting the herb containing the toxin. There is no guaranteed current way to confirm the absence of toxin from available herbal medicine. In 2018; four DNA sequences were identified in a large study as possible target areas to detect the toxin out of eleven different plants. These DNA sequences were bcL, matK, ITS2 and trnH-psbA (16). DNA barcoding is promising and ongoing way to detect most of the herbs that can be having the toxin, although it may still miss some uncommon herbs. CONCLUSIONS Aristolochic acid is a currently existing possible risk factor for the development of nephropathy and upper tract urothe- lial carcinoma. Its actual contribution to new cases diagnosed with upper tract urothelial carcinoma may be underesti- mated. Awareness programs to the public for possible herbal supplements contamination with Aristolochic acid as well as testing all herbal supplements for possible contamination should be implemented. DNA barcoding is able to identify most common herbs containing Aristolochic acid but may be still missing uncommon herbs. REFERENCES 1. Luciano RL, Perazella MA. Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment. Drug Saf. 2015; 38:55-64. 2. Jelakovic B, Dika Ž, Arlt VM, et al. Balkan endemic nephropathy and the causative role of aristolochic acid. Semin Nephrol. 2019; 39:284-296. 3. Rouprêt M, Babjuk M, Burger M, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2020 Update. Eur Urol. 2021; 79:62-79. 4. Zhong W, Zhang L, Ma J, et al. Impact of aristolochic acid exposure on oncologic outcomes of upper tract urothelial carcinoma after radical nephroureterectomy. Onco Targets Ther. 2017; 10:5775-5782. 5. 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Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2017; 34:135-144. 14. https://monographs.iarc.who.int/wp-content/uploads/2018/06/mono100A-23.pdf. Accessed online on January 17, 2022. 15. https://www.accessdata.fda.gov/cms_ia/importalert_141.html. Accessed online on January 18, 2022. 16. Dechbumroong P, Aumnouypol S, Denduangboripant J, Sukrong S. DNA barcoding of Aristolochia plants and development of species-specific mul- tiplex PCR to aid HPTLC in ascertainment of Aristolochia herbal materials. PLoS One. 2018; 13:e0202625. Correspondence Mohanarangam Thangavelu, MD - drtmohan@googlemail.com Asmaa Ismail, MD - asmaaismail0782@gmail.com Ahmed Zakaria, MD - aszakaria81@yahoo.com Hazem Elmansy, MD - hazemuro100@yahoo.com Walid Shahrour, MD - walid.shahrour@gmail.com Owen Prowse, MD - owenprowse@rogers.ca Ahmed Kotb, MD (Corresponding Author) - drahmedfali@gmail.com Urology Department, Northern Ontario School of medicine, 146 Court Street South, Thunder Bay, ON P7B 2X6, Canada.