Aristolochic Acid and Renal Toxicity

By Dónal P. O'Mathúna. Dr. O'Mathúna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship relevant to this field of study.

Early in 1992, two women in their 40s were treated for renal failure in a hospital in Brussels, Belgium. Both had been healthy and not recently taking any medications, although one had previously used a beta-agonist asthma inhaler for 8 years.1 They had both taken an herbal slimming remedy during 1990 and 1991 while attending the same medical clinic. A survey of all the Brussels dialysis units revealed seven additional young women with chronic interstitial nephritis who had used the same slimming regimen. While this situation was widely reported at the time, a 2008 report claims that the situation has developed into "a worldwide problem," with the culprit herbs still available for sale, especially on the internet.2 Clinicians with patients who have rapidly deteriorating renal function of unknown origin should be alert to the possibility of aristolochic acid nephropathy. Such patients should be asked about any herbal remedies they may have ingested in the previous couple of years, especially those of Chinese origin.

Background

The medical clinic at the center of the Belgian tragedy had changed the formula of its slimming aid in May 1990.1 The new remedy was to contain cascara powder, acetazolamide, belladonna extract, and two Chinese herbs, Stephania tetrandra and Magnolia officinalis. The latter were imported directly from China, and were not subject to quality control at that time in Belgium.1 Thus, the renal condition was initially called Chinese herb nephropathy. It is now believed that what was originally supplied as Stephania tetrandra was actually Aristolochia fangchi.3 This herb contains aristolochic acid, known to be nephrotoxic and carcinogenic in animals. For this reason, the clinical condition is now called aristolochic acid nephropathy (AAN).2

By 1998, more than 100 similar cases of rapidly progressive renal failure were diagnosed in Belgium and traced to the same clinic.3 This represents about 5% of those exposed to the slimming remedy. Why the toxins affect people so differently is one of the questions remaining unanswered about this tragedy. The 2008 report identified cases of AAN in several countries.2 However, the true extent of the problem remains unknown, especially in China and India where herbs containing aristolochic acid are frequently used and interchanged with other botanicals.

In 2000, it was reported that those with AAN were facing additional problems. Examination of renal tissue taken from the first two women with AAN who had received kidney transplants revealed urothelial carcinoma. Subsequently, 39 patients agreed to undergo prophylactic kidney transplantation. Among these, 18 cases of urothelial carcinoma were found (46%).4 All of the tissue samples removed from patients contained aristolochic acid adducts bound to human DNA, confirming that aristolochic acid was directly involved in the toxicity.

Availability

In response to the Belgian AAN outbreak, many countries banned the importation or sale of Aristolochia species. In 2000 and 2001, the FDA issued warnings to various stakeholders and an import alert on herbal products containing aristolochic acid.5 The FDA has also published a list of various scientific and Chinese names of herbs and products that may contain aristolochic acid.6

However, such regulatory actions have not removed the toxins from the market. In 2003, researchers at the University of California, Berkeley examined U.S. web sites and identified, among the items for sale, 19 products containing aristolochic acid and 95 products suspected of containing aristolochic acid.7 For a study published in 2004, other researchers purchased 25 aristolochia or asarum products from the web sites of U.S. merchants.8 The Asarum genus is closely related to aristolochia and contains aristolochic acid. Analyses revealed that six products contained aristolochic acid.

In the Netherlands, herbal products are prohibited from containing aristolochic acid. Dutch researchers purchased 68 herbal products with names associated with Aristolochia species or other species commonly replaced by Aristolochia species.9 Analyses found that 25 of the products (37%) contained aristolochic acid. All Aristolochia species have been banned in the United Kingdom since 2001.10 However, testing of herbal products available in the United Kingdom and labeled with Chinese names connected with aristolochia found that 40% of the samples contained aristolochic acid.11 Many products containing aristolochic acid remain on the market.

Naming Problems

As noted earlier, the original outbreak of AAN in Belgium was traced to the replacement of Stephania tetrandra by Aristolochia fangchi, and other problems in the naming of Chinese herbs.2 Both plants are known by the same common names in Pin Yin, the phonetic representation of Chinese characters.9 In addition, the two species are used interchangeably in traditional Chinese medicine.2

Lack of naming specificity is commonplace in traditional Chinese medicine. Several plant species can share the same Chinese common name, and some plants have more than one common name.11 Mistakes happen regularly. A case of AAN was reported in Hong Kong after a man consumed Aristolochia mollissima.12 This plant is known by two common names, Xun Gu Feng and Bai Mao Teng. However, Bai Mao Teng is also the common name for Solanum lyratum (also called Bai Ying). The Hong Kong man believed he had purchased Solanum lyratum, but was sold the poisonous Aristolochia mollissima material instead. A systematic study of Chinese herbs has revealed that this type of confusion occurs repeatedly because the Chinese naming system is not standardized and plant material is not authenticated at source.12

Mechanism of Action

Aristolochia species belong to the family Aristolochiaceae, several of which have been used in herbal remedies as anti-inflammatory agents.11 The toxic compounds in these species are a group of aristolochic acids, with the most abundant being named aristolochic acid I and aristolochic acid II. These compounds are found throughout the plant and have not been found outside the Aristolochiaceae family.11 Animal and human studies have found that aristolochic acids are nephrotoxic, carcinogenic, and mutagenic. Nephrotoxicity occurs in humans at mg/kg doses.11 The aristolochic acids are activated by metabolic enzymes within cells to give a highly reactive intermediate which forms covalent bonds with DNA.2 These adducts have been shown to cause mutations in animals and humans which probably trigger the growth of cancer. How aristolochic acid leads to renal damage remains unknown.2

A Related Condition

From the earliest reports of Belgian AAN, similarities were noted with another type of devastating renal disease. Balkan endemic nephropathy (BEN) affects thousands of men and women living in farming villages along the Danube river basin.13 Most cases occur in Bosnia, Bulgaria, Croatia, Romania, and Serbia. In contrast to AAN, this disease develops slowly, but leads to chronic renal failure with a strong association with urothelial cancer. The incidence is geographically restricted, and the disease is not inherited. Numerous environmental toxins have been proposed over the 50 years since the condition was first described, but none have satisfactorily explained the disease.2

The clinical and histological similarities between BEN and AAN have led to much research in this area. Aristolochia clematitis is a weed native to this Balkan area and grows among the wheat used to prepare local bread. Over several years, residents ingest similar amounts of aristolochic acid as those who took the Belgian slimming remedy. Tissue samples taken from BEN patients contain the same aristolochic acid adducts found in AAN patients. The same type of mutation has also been found in the cancer cells of patients with AAN or BEN. A connection between BEN and aristolochia was first noted by Serbian researchers in 1967, but appears to have been overlooked for decades.13 It has taken the recent Belgian tragedy to redirect research, leading to increasing confidence that the cause of BEN has been identified. The disease will hopefully be eradicated as efforts progress to eliminate Aristolochia clematitis from the area.

Conclusion

Efforts to eradicate aristolochia from herbal markets have not been successful. Outside of the original Belgian reports, many cases of AAN were reported after countries had banned the importation or sale of Aristolochia species.2 Regulatory efforts must continue to remove such products from the market.

Recommendation

Clinicians should remain alert to the possibility that rapidly progressing renal problems of unexplained origin may be related to consumption of herbal products. Chinese herbs are particularly prone to including Aristolochia species, and to the substitution of other species by Aristolochia species. The tragic example of aristolochia provides another reason why patients should be regularly asked about their consumption of herbal remedies and dietary supplements.

References

1. Vanherweghem JL, et al. Rapidly progressive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese herbs. Lancet 1993;341:387-391.

2. Debelle FD, et al. Aristolochic acid nephropathy: A worldwide problem. Kidney Int 2008;74:158-169.

3. Vanherweghem JL. Misuse of herbal remedies: The case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy). J Altern Complement Med 1998;4:9-13.

4. Nortier JL, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-1692.

5. U.S. Food & Drug Administration. Dietary supplements: Aristolochic acid, 2000-2001. Available at: www.cfsan.fda.gov/~dms/ds-bot.html. Accessed Oct. 7, 2008.

6. U.S. Food & Drug Administration. Listing of botanical ingredients of concern, 2001. Available at: www.cfsan.fda.gov/~dms/ds-bot2.html. Accessed Oct. 7, 2008.

7. Gold LS, Slone TH. Aristolochic acid, an herbal carcinogen, sold on the Web after FDA alert. N Engl J Med 2003;349:1576-1577.

8. Schaneberg BT, Khan IA. Analysis of products suspected of containing Aristolochia or Asarum species. J Ethnopharmacol 2004;94:245-249.

9. Martena MJ, et al. Enforcement of the ban on aristolochic acids in Chinese traditional herbal preparations on the Dutch market. Anal Bioanal Chem 2007;389:263-275.

10. U.K. Medicines and Healthcare products Regulatory Agency. List of herbal ingredients which are prohibited or restricted in medicines. Available at: www.mhra.gov.uk/home/groups/esherbal/documents/websiteresources/con009294.pdf. Accessed Oct. 7, 2008.

11. European Medicines Agency. Public statement on the risks associated with the use of herbal products containing Aristolochia species. London; 2005. Available at: www.emea.europa.eu/pdfs/human/hmpc/13838105en.pdf. Accessed October 7, 2008.

12. Zhao Z, et al. A systematic study on confused species of Chinese Materia Medica in the Hong Kong market. Ann Acad Med Singapore 2006;35:764-769.

13. Grollman AP, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007;104:12129-12134.