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use of herbal medicines containing AA, 3 Chinese herbs nephropathy and partly explaining the very high incidence of end-stage renal disease in Taiwan, Balkan endemic nephropathy: based on an excellent registration system covering the whole country. toward a single entity, aristolochic Several experimental models in rabbits, rats, and mice were able to reproduce the acid nephropathy nephrotoxic and carcinogenic eff ects of AA observed in humans. 4,5 Furthermore, Marc E. De Broe 1 the carcinogenic and mutagenic eff ects associated with the binding of metabolites Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy of ingested AA to DNA have been (BEN) are chronic tubulointerstitial renal diseases associated with extensively described in vitro and in vivo , urothelial carcinoma. The clinical expression and pathological lesions resulting in the classifi cation of AA as a 6 observed at different stages of CHN and BEN are strikingly similar. Both genotoxic carcinogen. Cosyns et al. 7 documented pathological have been linked to exposure to aristolochic acid (AA), a powerful evidence of urothelial malignancy and nephrotoxin and human carcinogen. Jelaković et al. present molecular overexpression of p53, a tumor suppressor epidemiological evidence relating urothelial carcinoma in patients with gene known to be mutated in several types BEN to dietary exposure to AA. It is time to abandon the terms ‘CHN ’ and of malignancies, in the removed kidneys ‘ BEN ’ and introduce ‘ aristolochic acid nephropathy’ to cover both clinical of almost all CHN patients. A high preva- conditions. lence of urothelial malignancy was con- fi rmed a year later in the series of Nortier Kidney International (2012) 81, 513 – 515. doi: 10.1038/ki.2011.428 et al. 8 Th e latter study also demonstrated that the risk of urothelial carcinoma was related to the cumulative intake of Chronic tubulointerstitial nephropathy toward end-stage renal failure. Further- A. fangchi , and that all patients exposed to associated with urothelial carcinoma is more, a strikingly higher prevalence rate AA had AA-related DNA adducts in speci- described in three clinical entities in the of women presenting with CHN is mens of renal tissue. renal literature: analgesic nephropathy, observed, whereas BEN is characterized Already in 2001, there was a call to Chinese herbs nephropathy (CHN), and by familial clustering ( Table 1 ). change the term ‘ Chinese herbs nephro p- Balkan endemic nephropathy (BEN). In 1991, nephrologists in the area athy’ to ‘ aristolochic acid nephropathy.’ 9 Bilateral calcifying renal papillary around Brussels, Belgium, noted an Balkan endemic nephropathy (BEN) is necrosis associated with interstitial increasing number of relatively young a tubulointerstitial nephropathy and was fibrosis and tubular atrophy resulting women who presented with different described already some 50 years ago. Th e in pronounced cortical retraction found degrees of renal failure. All had attended renal disease tends to occur in people in patients with long-term abuse of the same private ‘ slimming ’ clinic and had older than 18 years and in members of the combined analgesics associated with ingested a mixture of several drugs and same household, typically living in farm- addictive substances is characteristic of powdered extracts of Chinese herbs con- ing villages located near tributaries of the analgesic nephropathy (Table 1). Using taining Aristolochia fangchi. 2 Th e exposure Danube in the Balkan area and Romania. computed tomographic scanning without to the inadvertently added Aristolochia BEN has the same renal localization and contrast medium as renal imaging tech- plant containing aristolochic acid (AA) association with upper urinary tract nique allows a correct diagnosis for these turned out to be the most likely cause of malignancy that are observed in patients patients. 1 the renal injury and later development of with CHN.10 Th e clinical expression and pathological urothelial-cell atypia and carcinoma. Over the years an impressive number of lesions observed at different stages Very soon aft er the publication of the potential etiological agents (factors) have of CHN and BEN are strikingly similar index cases, patients presenting with a sim- been proposed, such as environmental except for the rate of their progression ilar clinicopathological entity were reported factors, mycotoxins (in particular, ochra- in several countries around the world. toxin A), heavy metals, viruses, and trace- 1Faculty of Medicine, University of Antwerp, A couple of years later, reports from metal defi ciencies. However, none of these Antwerpen , Belgium Taiwan and mainland China confi rmed studies collected or delivered convincing Correspondence: Marc E. De Broe, Faculty of Medicine, University of Antwerp, Campus Drie Eiken the high prevalence of chronic tubu- toxico-epidemiological data. Universiteitplein nr1, 2610 Wilrijk, B-2610 Antwerpen, lointerstitial renal disease in end-stage The ochratoxin A (OTA) hypothesis Belgium. E-mail: [email protected] renal failure patients associated with the was based on the fact that residents in

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Table 1 | D i ff erential diagnosis of some forms of chronic tubulointerstitial nephro- mutational spectra as biomarkers of expo- pathy associated with urothelial carcinoma sure to and carcinogenic eff ects of AA in the evaluation of the disease in countries Aristolochic acid nephropathy where Aristolochia species have been used Chinese herbs Balkan endemic Analgesic for medicinal purposes. nephropathy nephropathy nephropathy In summary, the etiology of CHN and Etiology Aristolochic acid Analgesics + addictive BEN is exposure to Aristolochia substances containing AA, a toxic component of all Course toward ESRF 6 months to 2 years > 20 years > 10 – 15 years Aristolochia species. Th e slower progres- Kidney imaging Shrunken, irregular Shrunken, smooth Shrunken, irregular sion toward end-stage renal failure of contours, no surface, no contours, papillary patients with BEN has to do with lower calci fi cations calci fi cations necrosis, calcifi cations doses of AA ingested during the con- Histology: sumption of contaminated bread as com- • Cellular infi ltra- + + + + pared with the high dose of AA found in tion the herbal mixtures used by patients in the • Fibrosis + + + + + + ‘ slimming ’ clinic. Th e higher prevalence • A t r o p h y + + + + + + + of women in the CHN cohorts can be attributed to the fact that young women Capillarosclerosis + + + are more likely to attend such clinics. Apoptosis + + + + ? Recently, the National Toxicology Urothelial + upper tract + upper tract + a Program reported that AA was carcino- malignancies genic to humans. Th e report suggested Familial − + − that ‘ sufficient ’ scientific evidence was occurrence available to conclude that exposure to AA a As long as phenacetin was part of the analgesic mixtures. ESRF, end-stage renal failure. causes urothelial cancer in humans through formation of DNA adducts endemic regions are exposed to relatively the dominance of the A:T ; T:A transver- (specifically, through binding of the high concentrations of OTA.11 However, sions in the p53 tumor suppressor gene reactive metabolite with adenine) and similar high exposure occurs throughout mutational spectrum, was a breakthrough the resulting transversion mutations in the world in farming communities that in the identifi cation of AA as an etiologi- oncogenes. 17 are largely free of chronic kidney disease cal agent of the upper tract malignancy The exact mechanism, however, by and urothelial malignancy. Furthermore, observed in BEN. 14 Th e observed muta- which exposure to AA results in chronic chronic nephrotoxicity associated with tional spectra in urothelial cancers among renal damage remains uncertain. dietary exposure to OTA has never been BEN patients resemble the mutational In a recent study in mice, chronic observed in humans. 12 ‘ signature ’ observed in cultured cells and administration of AA resulted in progres- Already in 1969 Ivić 13 proposed that rodents treated with AA.15 sive renal damage. AA was able to activate ingestion of fl our contaminated with seeds Jelakovi ć et al.16 (this issue) now extend Smad signaling to mediate epithelial– mes- from Aristolochia clematitis may be the their previous observations, 14 presenting enchymal transition and renal fi brosis via cause of BEN. He noted that seeds from molecular epidemiological evidence relat- both transforming growth factor- - these plants, which grew abundantly in ing urothelial-cell carcinoma of the upper dependent and JNK / MAP kinase-depend- local wheat fi elds, comingled with wheat urinary tract to dietary exposure to AA ent mechanisms. Th e blockade of JNK and grain during the harvesting process. He through the contamination of fl our pre- specifi c knock-down of Smad3, but not administered Aristolochia seeds to animals pared from locally grown wheat grain in Smad2, were able to attenuate AA-stimu- that developed renal damage, and specu- the endemic cohort. Aristolactam-DNA lated collagen matrix expression and epi- lated that human exposure to a toxic com- adducts were present in 70 % of the thelial– mesenchymal transition. 18 ponent of Aristolochia seeds could occur endemic cohort ( n = 67) and in 94 % of Lebeau et al.19 showed the involvement through ingestion of bread prepared with subjects with A:T ;T:A mutations in of AA in the early proximal tubular dys- fl our derived from contaminated grain. TP53. In contrast, neither aristolactam- function, such as low-molecular weight However, his fi eld surveys and data failed DNA adducts nor A:T; T:A mutations proteinuria, found in CHN. Th ey pro- to provide convincing evidence, and his were detected in tumors of upper urinary posed a causal relationship between DNA astute observations were neglected for tract carcinoma patients (n = 10) residing adduct formation, decreased megalin many decades. in non-endemic regions (regions not expression, and inhibition of receptor- Th e fi nding by Grollman and colleagues exposed to AA). mediated endocytosis of low-molecular of AA-derived DNA adducts in renal cor- Jelakovi ć et al. 16 propose a molecular weight proteinuria. tical and urothelial tumor tissue of patients epidemiological approach using deoxy- In acute aristolochic acid nephropathy with documented BEN, associated with adenosine-aristolactam adducts and TP53 in mice, it was found that the AA adducts

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2 . Vanherweghem JL , Depierreux M , Tielemans C et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993 ; 341: 387 – 391 . 3 . Li X , Wang H . Aristolochic acid nephropathy: what we know and what we have to do. Nephrology (Carlton) 2004 ; 9 : 109 – 111 . 4 . Cosyns J - P , Dehoux J - P , Guiot Y et al. C h r o n i c aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy? Kidney Int 2001 ; 59 : 2164 – 2173 . 5 . Debelle FD , Nortier JL , De Prez EG et al. Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002 ; 13 : 431 – 436 . 6 . Schmeiser HH , Pool BL , Wiessler M . Mutagenicity and in vitro metabolism of aristolochic acid. Biochem Pharmacol 1985 ; 34 : 455 – 456 . 7 . Cosyns J - P , Jadoul M , Squifflet J - P et al. Urothelial lesions in Chinese-herb nephropathy. Am J Kidney Dis 1999 ; 33 : 1011 – 1017 . 8 . Nortier JL , Martinez MC , Schmeiser HH et al. Figure 1 | Aristolochia plant from a copy by a Byzantine artist ( AD 512) of the treatise on Urothelial carcinoma associated with the use of a pharmacology of antiquity, De Materia Medica, written by the Greek military doctor Chinese herb ( Aristolochia fangchi) . N Engl J Med Dioscorides Pedanius ( AD 40 – 90). The copy is currently conserved at the National Library of 2000 ; 342 : 1686 – 1692 . Austria, Medias Graecas 1, in Vienna. 9 . Gillerot G , Jadoul M , Arlt VM et al. Aristolochic acid nephropathy in a Chinese patient: time to abandon the term “Chinese herbs nephropathy” ? Am J Kidney Dis 2001 ; 38 : E26 . 10 . Cosyns J - P , Jadoul M , Squifflet J - P et al. Chinese herbs nephropathy: a clue to Balkan endemic formed with DNA may lead to tubular substance with an ability to induce uro- nephropathy? Kidney Int 1994 ; 45 : 1680 – 1688 . epithelial cell apoptosis via p53-mediated thelial cancer. 11 . Radi ć B , Fuchs R , Peraica M et al. O c h r a t o x i n A signaling. 20 AA induced dephosphoryla- Aristolochic acid nephropathy remains in human sera in the area with endemic nephropathy in Croatia . Toxicol Lett 1997 ; 91 : tion of STAT3 and subsequent activation an underdiagnosed renal illness because of 105 – 109 . of p53 and tubular epithelial cell apopto- its lack of identifi cation in certain parts of 12 . Godin M , Fillastre JP , Simon P et al. Is ochratoxin sis. In contrast, overexpression of STAT3, the world. It remains an international pub- a nephrotoxic in human beings? Adv Nephrol Necker Hosp 1997 ; 26 : 181 – 206 . p53 inhibition, or p53 knock-down with lic-health problem that can be resolved only 13 . Ivi ć M . [Etiology of endemic nephropathy] small interfering RNA attenuated AA- through implementation of measures to (article in Croatian). Lijec Vjesn 1969 ; 91 : induced tubular epithelial cell apoptosis. halt the risk of exposure to this toxic herb. 1273 – 1281 . 14 . Grollman AP , Shibutani S , Moriya M et al. Th is supports the hypothesis that p53 pro- Th e renal community has to be made Aristolochic acid and the etiology of endemic motes renal injury in acute aristolochic aware of the proposed concept that ‘ CHN ’ (Balkan) nephropathy . Proc Natl Acad Sci USA 2007 ; acid nephropathy. Th ese results have to be and ‘ BEN ’ are limitative misnomers. 104: 12129 – 12134 . 15 . Schmeiser HH , Janssen JW , Lyons J et al. interpreted with caution with regard to Excellent toxico-epidemiological research, Aristolochic acid activates ras genes in rat tumors humans, in view of the slowly progressive the use of sophisticated biochemical at deoxyadenosine residues . Cancer Res 1990 ; 50 : 5464 – 5469 . character of the disease in patients. On the methodologies, and exchange of informa- 16 . Jelakovi ć B , Karanovi ć S , Vukovi ć -Lela I et al. other hand, experiments conducted on tion in the context of the globalization of Aristolactam-DNA adducts are a biomarker of tissue from patients with BEN indicate nephrology have proven that both clinical environmental exposure to aristolochic acid. Kidney Int 2012 ; 81 : 559 – 567 . that p53 is also activated. entities have a common etiology, that is, 17 . Aristolochic acids 12th Report on Carcinogens. Some important conclusions can be AA, justifying the use of ‘ aristolochic acid National Toxicology Program, Public Health inferred from the CHN and BEN stories. nephropathy’ to cover two clinical expres- Service, US Department of Health and Human Services, Research Triangle Park, NC, 2009, For more than 2500 years, the Aristolochia sions (CHN and BEN) of that disease. pp45– 49 . (birthwort) species were among the most Aristolochic acid nephropathy is an 18 . Zhou L , Fu P , Huang XR et al. Mechanism of extensively described medicinal plants in underdiagnosed and underestimated chronic aristolochic acid nephropathy: role of Smad3. Am J Physiol Renal Physiol 2010 ; 298 : the Chinese Ayuverdic, Egyptian, Greek chronic renal disease associated with a very F1006 – F1017 . (Figure 1), Coptic, and European litera- high risk of developing upper urinary tract 19 . Lebeau C , Arlt VM , Schmeiser HH et al. Aristolochic ture because of their association with a urothelial carcinoma, worthwhile to trace in acid impedes endocytosis and induces DNA adducts in proximal tubule cells. Kidney Int 2001 ; multitude of pharmacological activities. any patient with an unexplained unclassifi - 60: 1332 – 1342 . Remarkably, it was not until the end of able progressive decline in renal function. 20 . Zhou L , Fu P , Huang XR et al. Activation of p53 the eighteenth century that the fi rst obser- promotes renal injury in acute aristolochic DISCLOSURE acid nephropathy . J Am Soc Nephrol 2010 ; 21 : vations of nephrotoxicity related to the The author declared no competing interests. 3 1– 4 1. use of Aristolochia appeared in the litera- 21 . Grollman P , Scarborough J , Jelakovi ć B . 21 REFERENCES Aristolochic acid nephropathy: an environmental ture. Recently this magic plant turned 1 . De Broe ME , Elseviers MM . Analgesic nephropathy. and iatrogenic disease . Adv Mol Toxicol 2009 ; 3 : out to contain a powerful nephrotoxic N Engl J Med 1998 ; 338 : 446 – 452 . 211 – 226 .

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