NDT Advance Access originally published online on October 3, 2007
Nephrology Dialysis Transplantation 2008 23(1):39-41; doi:10.1093/ndt/gfm667
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Aristolochic acid: the common culprit of Chinese herbs nephropathy and Balkan endemic nephropathy*
Department of Nephrology and Renal Transplantation, University Hospital Gasthuisberg, Leuven, Belgium
Correspondence and offprint requests to: Yves Vanrenterghem, MD, PhD, Department of Nephrology and Renal Transplantation, University Hospital Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium. Tel: +32 16 344580; Fax: +32 16 344599; E-mail: yves.vanrenterghem{at}uz.kuleuven.ac.be
Keywords: aristolochic acid; Balkan endemic nephropathy; Chinese herbs nephropathy; urothelial malignancies
Balkan endemic nephropathy (BEN) is a devastating tubulointerstitial kidney disease affecting men and women living in rural areas of Bosnia–Herzegovina, Bulgaria, Croatia, Romania and Serbia [1]. The disease occurs exclusively in farming villages situated in valleys of the Danube River and its tributaries. Since its first description in 1956, the geographic distribution as well as other epidemiologic features have remained constant, including its focal occurrence in certain villages, its familial but not inherited character, the initial manifestation after residence in an endemic village for 15 years or more and the strong association with urothelial malignancies of the upper urinary tract. Despite the extensive research on the aetiology of BEN and the accompanying urothelial tumours, elegantly summarized by Stefanovic and co-workers in a recent review published in the American Journal of Nephrology [2], the cause of the disease remained a medical enigma. During the past 50 years both genetic factors and environmental factors including viruses, heavy metals, trace element deficiencies, mycotoxines (ochratoxin A), plant toxins (aristolochic acid) and polycyclic aromatic hydrocarbons from coal deposits (Pliocene lignite) have been proposed as possible aetiologic factors.
The hypothesis that aristolochic acid (AA), a nephrotoxic and carcinogenic plant alkaloid derived from Aristolochia species, could be a potential aetiologic factor for BEN was formulated as early as the 1970s, based on epidemiologic, environmental and agricultural research [3]. It was observed that Aristolochia clematitis, a plant native to the endemic region, often grows in cultivated fields where its seeds, containing AA, commingle with wheat grain during the annual harvest. As bread, the dietary staple of the region, is prepared traditionally from flour made from locally-grown wheat, residents of the endemic region consuming home-baked bread may be exposed, over time, to toxic amounts of AA [4,5].
In 1993 Vanherweghem et al reported in the Lancet an outbreak of a rapidly progressive tubulointerstital kidney disease in Belgian women who had followed the same slimming regimen in the same medical clinic in Brussels [6]. Since 1990 the prescribed slimming pills contained two herbs imported from China and therefore the disease was initially designated as ‘Chinese herbs nephropathy’ (CHN). Although in the original paper it was mentioned that AA could not be found in the slimming pills, later investigations clearly showed the pills contained AA, probably because one of the prescribed herbs, Stephania tetrandra (‘Han Fang-ji’), was inadvertently substituted by Aristolochia fangchi (‘Guang Fang-ji’) [7]. The detection of AA-specific DNA adducts in kidney and urinary tract tissues from patients with CHN unambiguously demonstrated exposure to AA [8–11]. Moreover, it provided the pathophysiologic clue as to the cause of the urothelial malignancies seen in a substantial part of these patients. Indeed, the 7-(deoxyadenosine-N6-yl)-aristolactam I adduct (dA-AAI) is a premutagenic lesion and is associated with mutations in genes involved in carcinogenesis such as the H-ras proto-oncogene and the p53 tumour-suppressor gene. In addition, rodents given AA developed similar clinical features, renal interstitial fibrosis and urothelial atypia as CHN patients, demonstrating the central role of AA in the pathogenesis of CHN [7].
From the very beginning it was obvious that both the clinical presentation and the histological findings of the now-called aristolochic acid nephropathy (AAN) are very similar to those observed in BEN (Table 1) [12]. This observation raised the possibility of a common cause for both diseases: AA. A pilot study in three patients living in the endemic region (two urothelial malignancies and one uretral stenosis) indeed showed dA-AAI adducts in kidney tissue in two out of three patients [13]. However, it was not clear whether these patients were actually suffering from BEN.
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In the July issue of PNAS Grollman and colleagues presented strong evidence that AA is indeed the cause of BEN and the associated urothelial malignancies [14]. Using a 32P-postlabeling/polyacrylamide gel electrophoresis technique, the authors identified the AA-derived DNA adducts dA-aristolactam (AL) and dG-AL in the renal cortex of four patients with BEN, but not in five patients with other chronic renal diseases or five patients with upper urinary tract malignancies living in non-endemic regions, for the first time proving AA exposure in BEN patients. Furthermore, dA-AL and dG-AL were detected in upper urinary tract malignancies of three long-term residents of endemic villages. The authors went further, delving into the mutational background of the urothelial malignancies. DNA was isolated from tumour tissue from 11 patients who had resided in endemic villages for at least 15 years and exons 2–11 of the tumour-suppressor gene p53 were sequenced. Nineteen base substitutions were identified. Importantly, mutations at A:T pairs accounted for 89% of all p53 mutations, with 78% of these being A:T
T:A transversions. This mutational ‘fingerprint’ is also seen in cultured cells and in rodents treated with AA [15]. Of note, histopathologic analyses of the renal cortex of these patients showed changes that were diagnostic or highly suggestive of BEN in eight out of nine patients (insufficient tissue in two patients). That AA produced by A. clematitis is the cause of BEN is an old hypothesis, which was more recently supported by the research in AAN. However, Grollman et al are the first to provide ‘direct’ instead of ‘circumstantial’ evidence that AA is indeed the ‘culprit’ of BEN. Furthermore, they provide some true mechanistic insights into how exposure to AA can cause the associated urothelial malignancies. Two major questions remain to be explored. First, it is currently unclear why only 2–5% of the people living in the endemic regions is affected by the disease, although a substantially larger number of individuals is likely to have been exposed to toxic amounts of AA. A large genetic component in the susceptibility to the disease has been suggested, but further research is warranted. Second, the proposed way of exposure, although plausible, remains to be proven by the detection of AA in flour and bread from the endemic region, which might be impossible given the presumably very low concentrations of AA in these products. The good news, however, is that if the AA hypothesis holds true, we can expect the incidence of BEN and the associated urothelial tumours to decrease over the years to come, because both agricultural developments (i.e. introduction of herbicides, new harvesting techniques) and lifestyle changes (i.e. diminished daily intake of bread, fewer families baking their own bread) will most likely lead to a decrease in dietary exposure to AA. In the meantime public health authorities in the affected countries should implement measures to remove the potential source of AA from contaminated grain, like some countries banned the use of herbs containing AA following the Chinese herbs disaster in Belgium [16].
Conflict of interest statement. None declared.
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*Comments on Grollmann AP, Shibutani S, Moriya M et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proceedings of the National Academy of Sciences (PNAS) 2007;104:12129–12134.
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[Abstract/Free Full Text] - Arlt VM, Stiborova M, Brocke JV, et al. Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer. Carcinogenesis. Advance Access 2007; doi:10.1093/carcin/bgm082.
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Accepted in revised form: 30. 8.07
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