Nephrotoxicity and Chinese Herbal Medicine

Bo Yang,1,2 Yun Xie,2,3 Maojuan Guo,4 Mitchell H. Rosner,5 Hongtao Yang,1 and Claudio Ronco2,6

Abstract Chinese herbal medicine has been practicedfor the prevention, treatment, andcure of diseases forthousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the 1Department of nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, Nephrology, First flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of Teaching Hospital of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Tianjin University of Traditional Chinese Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, Medicine, Tianjin, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy China; 2International metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney Renal Research injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in Institute of Vicenza and 6Department of patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic Nephrology, Dialysis acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening. and Transplantation, Clin J Am Soc Nephrol 13: 1605–1611, 2018. doi: https://doi.org/10.2215/CJN.11571017 San Bortolo Hospital, Vicenza, Italy; 3Department of Nephrology, Xin Hua Introduction assess (7). However, in total, drug-related nephrotox- Hospital Affiliated to According to the World Health Organization (1), icity has been reported to contribute to about 26% of Shanghai Jiaotong traditional medicine is either the mainstay of medical cases in patients with hospital-acquired AKI and 18% University School of Medicine, Shanghai, treatment or serves as a complement to it in up to of cases in patients with community-acquired AKI 4 – China; School of 75% 80% of the world population, mostly in the de- globally. The critically ill patients with drug-induced Integrative Medicine, veloping world (2). Traditional medicine, including AKI usually need to RRT; the contribution of Chinese Tianjin University of traditional Chinese medicine, has been practiced for herbal medicine to these figures is not clear (8). Adverse Traditional Chinese the prevention, treatment, and cure of disorders or event reporting is generally voluntary, and toxicity has Medicine, Tianjin, China; and 5Division diseases for thousands of years (3) and for many kinds been documented through patients reports and series of Nephrology, of diseases (4). Importantly, Chinese herbal medicine is (interestingly, most of which are not from China). This University of Virginia an important component of traditional Chinese medi- paucity of data often leads to a false sense of re- Health System, cine, and it has become popular all over the world as assurance that nephrotoxicity is a rare event when, in Charlottesville, Virginia a source of alternative therapies. The available data fact, few data exist. This article will focus on the kidney suggest that the traditional Chinese medicine market toxicity of Chinese herbal medicine. Nephrotoxicity Correspondence: is large and that Chinese herbs have been exported to caused by other traditional medicines, which are not Dr. Hongtao Yang, over 175 countries and regions, including Japan, South used frequently in China, is beyond the scope of this Department of Korea, India, Germany, Holland, other European coun- review. Nephrology, First tries, and the United States (5). The total market value Teaching Hospital of of Chinese materia medica was estimated to amount Tianjin University of Traditional Chinese to United States $83.1 billion in 2012, an increase of Chinese Herbal Medicines Associated with Medicine, 88 .20% from the previous year (1). Therefore, the effect of Nephrotoxicity Changling Road, herbal medicine use is global and expanding. Given There is a substantial amount of basic research Xiqing district, 00381 the potential hazardous implications of the use of non- centered on the nephrotoxicity associated with Chinese Tianjin,China,orDr. – Claudio Ronco, San Food and Drug Administration (non-FDA) approved herbal medicine use over the last two decades. The main Bortolo Hospital, Viale supplements, it is important to increase global aware- nephrotoxic components from herbs are aristolochic Rodolfi, 37, IT–36100 ness about herbal medicine. acids (Figure 1) (structure of aristolochic acid) and Vicenza, Italy. Email: Chinese herbal medicine is composed mainly of alkaloid compounds (9,10). Aristolochic acids are a [email protected] or natural compounds with complex active ingredients family of carcinogenic, mutagenic, and nephrotoxic [email protected] that can lead to varying degrees of side effects (3). Some phytochemicals, and they are mainly derived from the of these herbal medicines are also known to cause birthwort family of plants (Aristolochia contorta Bunge, nephrotoxicity, which is often overlooked by physicians Aristolochia manshuriensis Kom, Clematis Chinensis Osbeck, and patients due to the belief that herbal medications and Aristolochia cathcartii Hook). Nephrotoxic alkaloids are innocuous (6). The incidence of kidney injury are derived from Tripterygium regelii Sprague et Takeda, induced by Chinese herbal medicines is difficult to Stephania tetrandra S. Moore, Strychnos nux-vomica Linn, www.cjasn.org Vol 13 October, 2018 Copyright © 2018 by the American Society of Nephrology 1605 1606 Clinical Journal of the American Society of Nephrology

casts. Again, no other etiologies for these toxicities could be found. Horoz et al. (15) reported on a patient with multisys- tem hypersensitivity reaction and progressive AKI associated with the consumption of Crataegus orientalis or hawthorn. In this patient, the kidney biopsy revealed acute interstitial nephritis (16). A more recent compound associated with AKI is andrographolide. Andrographolide, the primary compo- nent of a traditional medicinal herb Andrographis paniculata (chuan xin lian) is widely used in China for the treatment of upper and lower respiratory tract infection and dysentery. In 2014, Zhang et al. (13) published a systemic analysis review of the Chinese literature from January 1978 to August 2013 that included 26 patient reports of andrographolide-induced AKI. The major pathologic finding associated with AKI in these patients was acute tubular necrosis. The mechanism of andrographolide-induced AKI is not clear.

Chinese Herbal Medicine and CKD The compound that has most tightly linked chronic kidney injury and Chinese herbal medicine is aristolochic acid. Recognizing the link, the condition has been termed Chinese herbal nephropathy. Vanherweghem and colleagues Figure 1. | Structure of aristolochic acid, one of the main compo- (17) first described progressive chronic interstitial fibrosis and nents of nephrotoxicity of Chinese herbs. advanced kidney failure in nine young Belgian women who were using Chinese herbal slimming remedies. Kidney biopsies and Aconitum carmichaeli Debx. In addition, Chinese herbal done in eight of these women revealed extensive interstitial medicine may contain anthraquinones, flavonoids, and fibrosis with minimal glomerular changes. More patients with glycosides that have nephrotoxicity. A list of Chinese herbal similar findings soon came to light, and aristolochic acid was medicines known to contain aristolochic acid, alkaloids, and identified as the likely causative agent (10,17,18). Since then, other nephrotoxic components is given in Table 1. patients with aristolochic acid nephropathy have been reported worldwide, most of whom are from Asia (19–22). A retro- spective study of 86 patients with aristolochic acid nephrop- Manifestation of Nephrotoxicity Associated with athy reported that 87% (67 patients) present with CKD and that Chinese Herbal Medicines 22% (19 patients) presented with AKI (23). Nephrotoxicity associated with Chinese herbal medi- Excessive intake of aristolochic acid is a major cause of cines includes AKI, CKD, nephrolithiasis, rhabdomyolysis, aristolochic acid nephropathy and Balkan nephropathy, Fanconi syndrome, and urothelial carcinoma. Representa- which is a chronic tubulointerstitial disease associated with a tive patient reports of these nephrotoxic manifestations are high frequency of urothelia atypia, occasionally culminating listed in Table 2. in tumors of the kidney pelvis and urethra. In contrast to the classic presentation of aristolochic acid nephropathy, which AKI is characterized by a rapid decline in kidney function (6 Nephrotoxicity associated with Chinese herbal medicine months to 2 years), Balkan nephropathy is slowly progres- is mostly reported through patient reports or patient series. sive (10–20 years), likely due to low-level exposure (18). In In many patients, the exact pathology associated with AKI addition to AKI and CKD, the clinical manifestations of is not well understood, but in others, a diagnosis has been aristolochic acid nephropathy also include proximal tubular made on the basis of kidney biopsy or other clinical obser- dysfunction (glycosuria and increased excretion of low vations that substantiate a clear mechanism of injury. In molecular weight proteins), hypertension, severe anemia, several patients, the most common causes of AKI were metabolic acidosis, small kidneys on kidney ultrasound, acute tubular necrosis and acute interstitial nephritis (11– and a high risk of urothelial malignancies, with estimated 14). Several representative patients are discussed. rates of 40%–46% (17,21,22). The cumulative dose of aristo- Lin and Ho (11) reported on two patients with AKI lochia, being a women, and a genetically determined pre- induced by sciadopitysin, a type of flavonoid extracted disposition toward carcinogenesis put patients at higher risk from Taxus cerebica, which was used for treating diabetes for urothelia malignancies (18,24). mellitus. In these patients, kidney biopsy showed acute In vivo and in vitro experiments have elucidated the interstitial nephritis with acute tubular necrosis. Lee et al. operative mechanism of aristolochic acid nephropathy: (1) (14) reported a case where a patient developed AKI, acute endoplasmic reticulum stress and injury (9,25), (2)oxida- hepatic failure, autoimmune hemolytic anemia, and throm- tive stress injury (26), (3) immune-mediated inflammatory bocytopenia after oral intake of a hot water extract of mechanism (27), and (4) kidney tubular epithelial cell Cupressus funebris Endl (mourning cypress), which is rich transdifferentiation (20). Thus far, there are no effective in flavonoids. Her kidney biopsy (Figure 2) showed acute therapies, but patients with aristolochic acid nephropathy tubular necrosis, interstitial nephritis, and hemoglobin require periodic screening for uroepithelial malignancies. Clin J Am Soc Nephrol 13: 1605–1611, October, 2018 Nephrotoxicity and Chinese Herbal Medicine, Yang et al. 1607

Table 1. Chinese herbal medicines known to contain kidney toxicity components (9,10)

Active Ingredients Latin Name English Name Chinese Name

Aristolochic acid Aristolochiaceae Aristolochic Ma douling Aristolochic acid Aristolochia debilis Sieb. et Zucc. Radix aristolochiae Qing muxiang Aristolochic acid Aristolochia obliqua S. M. Hwang Fangchi Guang fangji Aristolochic acid Aristolochia manshuriensis Kom Manshuriensis Guan mutong Aristolochic acid Aristolochia cinnabarina Root of Kaempfer Zhu shalian C. Y. Cheng et J. L. Wu Dutchmans pipe Aristolochic acid Aristolochia mollissima Hance Aristolochia Xun gufeng Aristolochic acid Clematis Chinensis Osbeck Radix clematidis Wei lingxian Aristolochic acid Asarum heterotropoides Fr. Schmidt var. Asarum sieboldii Xixin mandshuricum (Maxim.) Kitag Aristolochic acid Aristolochia cathcartii Hook Aristolochia Fangji Tripterygine Tripterygium regelii Sprague et Takeda Tripterygium Lei gongteng Calycanthine Chimonanthus praecox (Linn.) Link Chimonanthus La meigen Tetrandrine Stephania tetrandra S. Moore Tetrandra Fen fangji Dauricine Menispermum dauricum DC Menispermi Bei dougen Brucine Strychnos nux-vomica Linn Strychnos Ma qianzi Strychnine Strychnos nux-vomica Linn Strychnos Ma qianzi Veratrine Leucothoe griffithiana C.B. Clarke Wood veratry Mu lilu Aconitine Aconitum carmichaeli Debx Aconitum Wutou Pyrrolizidine alkaloids Senecio scandens Buch-Ham Groundsel Qian liguang Aconitine Aconitum tanguticum (Maxim.) Stapf Monkshood Fuzi Croton oil Croton caudatus Geisel. Croton Croton Ba dou Anthraquinone compounds Cassia obtusifolia L. Cassia Jue mingzi Anthraquinone compounds Cassia angustifolia Vahi Folium senne Fan xieye Anthraquinone compounds Rheum officinale Baill Rhubarb Da huang Chamaejasme flavonoids Euphorbia fischeriana Steud Stellera chamaejasme Lang du Podophyllotoxin Dysosma versipellis (Hance) Dysosma Ba jiaolian M. Cheng ex Ying Alisol A 24-acetate Alisma plantago-aquatica Linn Alisma Zexie Brucea alcohol Brucea mollis Wall Brucea Ya danzi Bakuchiol Psoralea corylifolia Linn Psoralen Bu guzhi Geniposide Gardenia jasminoides Ellis Gardenia Zhizi Esculentoside A Phytolacca acinosa Roxb Pokeberry foot Shanglu

Other links between Chinese herbal medicine and CKD hypokalemia with elevated creatine phosphokinase and include (1) chronic hypokalemic nephropathy associated myoglobin levels. In another case (29), a 29-year-old woman with the cough suppressant Glycyrrhiza glabra (licorice) (28– who consumed 30 licorice tablets per day for 4 months to 30) and (2) chronic interstitial nephritis and tubular atrophy lose weight developed muscle pain and was found to have associated with prolonged use of a Chinese herbal slim- AKI with hypokalemia and an elevated creatine phospho- ming pill containing anthraquinone derivatives extracted kinase. A kidney biopsy in this patient revealed severely from rhubarb (Rhizoma rhei) (31). damaged tubular cells with intense vacuolar formations. The other compound associated with rhabdomyolysis is E. sinica Nephrolithiasis (ephedra/ma huang). In one representative case (34), a healthy Chinese herbal medicine–induced nephrolithiasis is 21-year-old US Army soldier developed extreme elevations of not known to be very common. There are two published creatine phosphokinase as well as AKI after regularly ingesting patient reports of kidney stones associated with Ephedra two tablets of an herbal supplement containing ephedra every fi sinica (ephedra/ma huang), which is a very popular herb in day for a month to improve his physical tness test. treatment of respiratory conditions (4). Both patients were young adult men with a history of ingesting 40–3000 mg/d Factors Influencing Nephrotoxicity Associated with ephedra over several months (32,33). The components of Chinese Herbal Medicine the kidney stones in these patients were ephedrine, nor- An interesting observation is that not all people using ephedrine, and pseudoephedrine. Because of these events Chinese herbal medicine develop AKI or CKD, and there and other adverse events associated with ephedra, in April are several factors that may contribute to the ultimate 2004, the FDA prohibited the sale of ephedra-containing nephrotoxicity of these compounds (Figure 3) (factors dietary supplements in the United States (30). influencing the development of kidney disease associated with Chinese herbal medicine). Rhabdomyolysis There are several associations between rhabdomyolysis Intrinsic Toxicity of Herbs and Incorrect Identification of and Chinese herbal medicine use. G. glabra (licorice)–induced Potentially Toxic Compounds AKI secondary to rhabdomyolysis has been reported. In one There are misconceptions and mislabeling regarding case (28), a 78-year-old man who consumed 280 mg/d of particular Chinese herbal medicines that have led to serious licorice for 7 years was hospitalized for muscle pain and AKI. health consequences. These errors can lead to important The initial laboratory results revealed pronounced exposures with a high risk of toxicity. For instance, the root 1608 Clinical Journal of the American Society of Nephrology

Table 2. Chinese herbal medicines associated with nephrotoxicity

Possible Toxic English Name/ Latin Name Indications Kidney Manifestations Refs. Compound Chinese Name

Aristolochic acid Aristolochia spp. Aristolochia, To induce weight loss, Chronic interstitial 19–22,43 Guan Mu liver disease, nephritis, renal tong, Han arthritis, headache, interstitial fibrosis, Fang Ji edema Fanconi syndrome, urothelial carcinoma Flavonoid Taxus cerebica Chinese yew Diabetes, vascular Acute tubular necrosis, 11 (sciadopitysin) diseases acute interstitial nephritis Flavonoid Cupressus funebris Mourning Vascular diseases, Acute tubular necrosis, 14 Endl cypress instead of “yew” acute interstitial nephritis Flavonoid Crataegus orientalis Hawthorn Congestive heart AKI 15 oligomeric failure, hypertension, procyanthins hyperlipidemia Ephedrine, Ephedra sinica Ma huang Cough, to induce AKI, nephrolithiasis 32–34,44 norephedrine, weight loss, to cause pseudoephedrine sexual arousal Glycyrrhetinic acid, Glycyrrhiza glabra Licorice Cough, sore throat, Acute tubular necrosis, 28–30,45 glycyrrhizic acid Gancao arthritis, to induce hypokalemic weight loss nephropathy, Fanconi syndrome Anthraquinones, Rhizoma rhei Rhubarb Laxative, anti- Interstitial fibrosis, 31,45 oxalic acid inflammatory tubular atrophy Active moiety Tripterygium Lei Gong Teng Arthritis, anti- Acute tubular necrosis 46 triptolide wifordii inflammatory, immunosuppressant Oxidative Aloe capensis Cape aloe Constipation, insect Acute tubular necrosis, 31,45 degradation bites parenchymatous products nephritis Colchicine Colchicum Autumn crocus Gout AKI 47 autumnale Dioscorine, dioscine Discorea quartiniana Yam Taken as food, to cause Acute tubular necrosis 48 poisoning or induce suicide Irritant chemicals in Euphorbia Spurge Edema, to induce Acute tubular necrosis 12,49 the latex of the matabelensis, abortion plant Euphorbia paralias Andrographolide Andrographis Chuan-Xin- Infectious disease, such AKI, acute tubular 13 paniculata Lian (heart as upper and lower necrosis piercing respiratory tract lotus) infection, acute enteritis, bacillary dysentery of Asarum (xi xin) has a low level of aristolochic acid and herbalists and when modern analytical technologies for has been commonly used in traditional Chinese medicine confirmation of safety are used (39). formulations as an analgesic to treat headache, toothache, and other inflammatory diseases. However, the whole Incorrect Processing or Storage and Adulteration Asarum plant has a high level of aristolochic acid and can be The majority of Chinese herbal medicine compounds mistakenly used in manufacturing to yield an herbal must undergo physical and/or chemical pretreatment product with high risk of nephrotoxicity (35). In another processes that are critical for preservation, detoxification, example, .100 women in Belgium and France were reported or enhancing efficacy (3,39). These processes include sun to have suffered extensive interstitial fibrosis of the kidneys drying, roasting, wine frying, vinegar frying, steaming, after ingesting a weight loss regimen involving Chinese fumigation, and other processing techniques that may not herbal medicine from 1990 to 1992. The investigation into be known. Incorrect processing techniques may contribute these patients found that one of the herbs in the pills, Stephania to nephrotoxicity. For example, Carthamus tinctorius has tetrandra (fen fang ji or han fang ji), was inadvertently replaced recently been found to be contaminated with Auramine O during manufacturing by Aristolochia fangchi (guang fang dye, which was used to help retain its color so that it could ji), which contains very high levels of aristolochic acid yield a higher retail price. However, Auramine O is a (36,37). Caulis aristolochiae manshuriensis (guan mu tong), “nonedible” substance, and it is known to be a carcinogenic which also contains aristolochic acid, inadvertently replaced industrial dye that can cause kidney and liver toxicity (39). Lardizabalaceae (mu tong) in a traditional Chinese medicine Unexpected nephrotoxicity induced by some Chinese formula and also caused nephrotoxicity in patients (38). These herbal medicines may be associated with poor storage types of errors are generally not committed by experienced conditions, which may cause alteration of the chemical Clin J Am Soc Nephrol 13: 1605–1611, October, 2018 Nephrotoxicity and Chinese Herbal Medicine, Yang et al. 1609

For example, mice exposed to the traditional Chinese medicine niu huang jie du pian, which contains realgar (As4S4), developed severe hepatic and kidney injury (40). In addi- tion, arsenic and mercury were found to exceed the normal limits in some Panax notoginseng (san qi) samples (39,41). The exact role of heavy metal contamination in nephrotox- icity and how common this may be are unknown.

Prevention and Treatment The first principle of effective therapy is prevention of toxicity, which relies on the following critical issues (Table 3): (1) safe manufacturing processes that ensure high standards that avoid contamination with dangerous substances as well as clear labeling as to what compounds (and how much) are present in the herbal medicine, (2) licensing of practitioners to Figure 2. | Histologic picture of a case of AKI after oral intake of a hot ensure knowledge of traditional Chinese medicines and their water extract of Cupressus funebris. The figure shows glomeruli are potential side effects, (3) limitations on the dose and length of essentially normal. Kidney tubules show thickened tubular basement therapiesaswellasappropriatemonitoringforadverseeffects, membrane, and many epithelial cells are missing, necrotic, or flattened. and (4) development of a clear understanding regarding the Hemoglobin casts, interstitial fibrosis, and cellular infiltrate also are potential interactions between herbal medicines and other identified (periodic acid–Schiff stain). Original magnification, 3200. medications (42). For instance, there were two patient reports describing nonsteroidal anti-inflammatory drug–induced nephrotoxicity that was exacerbated by concomitant exposure composition of the compounds (6). For instance, oxidative to nonsteroidal anti-inflammatory drugs and herbal medicines degradation products related to Aloe species were found in a (31). These interactions have not been well cataloged and type of Chinese herbal medicine stored in ambient heat in present a clear danger to patients who may be taking multiple a plastic bottle. This inadequately stored herbal medicine “Western” and traditional Chinese medications. induced AKI because of severe vomiting and dehydration (6). When nephrotoxicity is encountered, treatment follows general principles for patients with AKI, including sup- Contamination by Heavy Metals portive care, avoidance of further nephrotoxin exposure, Chinese herbal medicines may also absorb unknown and attention to fluid and electrolyte balance. Given the environmental contaminants, such as heavy metals like arsenic, risks of CKD in these patients, longitudinal follow-up is cadmium, lead, and mercury, which may be hazardous (6,39). needed to monitor kidney function. In those patients who

Figure 3. | Factors influencing the development of kidney disease associated with herbal medicine. The figure shows herb-related, treatment, and patient factors which may contribute to nephrotoxicity of hebal medicine. 1610 Clinical Journal of the American Society of Nephrology

Table 3. Methods to prevent nephrotoxicity associated with herbal medicine

N Main Principles

1 Increased attention should be given to the possible nephrotoxicity associated with herbal medicine, the appropriate preparation, the comedication that has already been prescribed to the patient 2 Preclinical pharmacologic and toxicologic assessment of herbal medicine is recommended before widespread use 3 Extreme caution should be observed when using herbal medicine associated with nephrotoxicity 4 Avoid herbal medicine overdosage and long-term use 5 Carefully record all cases of adverse reactions (e.g., kidney function, allergy) 6 Develop a much stronger and more stringent system to manage toxicity in herbal medicine may have been exposed to aristolochic acid, periodic 5. Teng L, Zu Q, Li G, Yu T, Job KM, Yang X, Di L, Sherwin CM, screening for uroepithelial cancer must be undertaken. Enioutina EY: Herbal medicines: Challenges in the modern world. Part 3: China and Japan. Expert Rev Clin Pharmacol 9: 1225–1233, 2016 6. Luyckx VA: Nephrotoxicity of alternative medicine practice. 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Zhang WX, Zhang ZM, Zhang ZQ, Wang Y, Zhou W: An- herbal medicine is an example of how such practice is also drographolide induced acute kidney injury: Analysis of 26 cases reported in Chinese Literature. Nephrology (Carlton) 19: 21–26, common in other parts of the world. Nephrologists should 2014 always be encouraged to obtain a detailed history of sup- 14. Lee JJ, Chen HC: Flavonoid-induced acute nephropathy by plements other than prescribed medications, including (but Cupressus funebris Endl (Mourning Cypress). Am J Kidney Dis 48: not limited to) Chinese herbal medicine, regardless of the e81–e85, 2006 ’ 15. Horoz M, Gok E, Genctoy G, Ozcan T, Olmaz R, Akca M, Kiykim patients ethnic background. Increased global awareness is A, Gurses I: Crataegus orientalis associated multiorgan hyper- important, because recognition and managing this entity will sensitivity reaction and acute renal failure. Intern Med 47: help build the body of evidence to develop effective therapies. 2039–2042, 2008 16. Crataegus oxyacantha (Hawthorn). Monograph. Altern Med Rev 15: 164–167, 2010 17. Debelle FD, Vanherweghem JL, Nortier JL: Aristolochic acid Acknowledgments nephropathy: A worldwide problem. Kidney Int 74: 158–169, This work was supported by National Natural Science 2008 Foundation of China grants 81774065 and 81303092. 18. Jadot I, Decle`ves AE, Nortier J, Caron N: An integrated view of aristolochic acid nephropathy: Update of the literature. IntJMol Sci 18: E297, 2017 Disclosures 19. Hong YT,Fu LS, Chung LH, Hung SC, Huang YT,Chi CS: Fanconi’s None. syndrome, interstitial fibrosis and renal failure by aristolochic acid in Chinese herbs. Pediatr Nephrol 21: 577–579, 2006 20. Yang L, Li X, Wang H: Possible mechanisms explaining the ten- References dency towards interstitial fibrosis in aristolochic acid-induced 1. 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