Aristolochic acid nephropathyBMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e4000 (Published 15 June 2012) Cite this as: BMJ 2012;344:e4000
- M Refik Gökmen, National Institute for Health Research clinical lecturer in renal medicine1,
- Graham M Lord, professor of medicine1
- 1Division of Transplantation Immunology and Mucosal Biology, King’s College London, London SE1 9RT, UK
More than 20 years ago a Belgian report described nine women with rapidly progressive fibrosing interstitial nephritis who either required dialysis or showed progressive renal impairment.1 All of the women had taken a slimming regimen that included herbs of the Aristolochia family, which have been known to be nephrotoxic and carcinogenic since the 1980s. Within five years, this group of nephrologists identified more than 100 patients with aristolochic acid nephropathy, almost half of whom were later found also to have tumours of the upper urinary tract.2 Case reports and series from around the world followed.3 Aristolochic acid was classified as a human carcinogen by the International Agency for Research on Cancer, and regulatory authorities in Europe, North America, and several other regions issued alerts or instituted import bans. However, these regulatory measures have been wholly inadequate at eliminating this preventable disease, with a recent report describing 300 cases of aristolochic acid nephropathy from a single centre in Beijing.4
Herbs that contain aristolochic acid are often found in traditional Chinese preparations, particularly—although not exclusively—in those with fang ji and mu tong as listed ingredients, often as a result of inadvertent adulteration.5 Epidemiological surveys from the People’s Republic of China have shown that chronic kidney disease is becoming more prevalent, with more than 100 million people in this region now estimated to be affected.6 It can be difficult to identify potential sources of aristolochic acid in traditional remedies, making the contribution of this substance to the epidemic of chronic kidney disease a challenge to estimate. A recent analysis of the Taiwan national health insurance database found that about 40% of Taiwanese people had consumed products either known or likely to contain aristolochic acid between 1997 and 2003, with a marked dose-response relation between estimated aristolochic acid exposure and risk of end stage renal disease and urothelial cancer (Pu Y. Aristolochia-related nephropathy and urothelial carcinoma. Abstract presented at Aristolochia-related nephropathy and urothelial cancer, Taipei, 7 January 2012). The medicinal use of most plant species that contain aristolochic acid has been banned in Hong Kong, Taiwan, Malaysia, and mainland China, although certain products containing this compound are still permitted in China under the supervision of Chinese medicine practitioners. In some parts of the world the extent of human exposure to aristolochic acid is still not known. Plants that contain aristolochic acid are used in folk medicine in India and parts of Africa.5 Although the risk of nephropathy and cancer increases with dose and cumulative exposure, current evidence does not allow the definition of a safe dose.
Another dimension in the growing appreciation of aristolochic acid as an important cause of kidney disease and cancer worldwide has come with its identification as the causative agent of Balkan endemic nephropathy, a form of tubulointerstitial renal disease associated with cancer that affects tens of thousands of patients in the Danube basin. The contamination of wheat flour in affected villages by the seeds of the weed Aristolochia clematitis was first noted in 1969.7
Despite measures to regulate aristolochic acid in Western countries, cases of aristolochic acid related nephropathy continue to occur, and patients are able to take products containing aristolochic acid for many years. A recent Australian report described an ultimately fatal case of aristolochic acid related nephropathy in a patient who took herbal products bought by mail order even after a 2002 ban on products suspected of containing the substance.8
In the United States, herbal medicinal products are still classified as “dietary supplements” and are regulated by the Dietary Supplement Health Education Act of 1994. The Food and Drug Administration issued an alert in 2001 warning consumers and the herbal medicine industry of the dangers of aristolochic acid; although some products containing aristolochic acid have been seized, consumers in the US and worldwide can still obtain many products freely over the internet. The regulatory framework in the European Union is somewhat more comprehensive—the 2004 Traditional Herbal Products Directive requires that all traditional herbal drugs are registered and approved, with a demonstration of safety and efficacy. However, a recent investigation by the Medicines and Healthcare Products Regulatory Authority in the United Kingdom showed that aristolochic acid was still present in preparations of various herbal remedies,9 and the judge in a recent UK court case recommended that the supply of this substance be more closely regulated.10
Although it is challenging to regulate a global market in herbal medicinal products, the threat to public health posed by products that contain aristolochic acid highlights the importance of ensuring that comprehensive listings of ingredients must be made mandatory for herbal products and data must be collected on their effects. National agencies should improve their surveillance of internet outlets and regularly test available products. The public also needs to be more aware of the potential risks associated with the unregulated use of herbal medicines, just as the wider medical community needs to be more aware of the toxic effects of aristolochic acid. The lack of internationally agreed diagnostic criteria or management guidelines for aristolochic acid nephropathy means that optimal epidemiological, preventive, and therapeutic strategies have not yet been developed, even though this disease may affect millions of people worldwide. Coordinated international action could help to ensure that it is eradicated.
Cite this as: BMJ 2012;344:e4000
Competing interests: Both authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Not commissioned; externally peer reviewed.