The nephrotoxicity of aristolochic acid was documented in a clinical trial when it was tested for cancer therapy.(11) Later research has shown its in vitro genotoxicity and carcinogenicity.(12)

All these cases of nephropathy can be traced to the ingestion of the herbal drug preparation produced by the same clinic, containing the incorrect substituted herbal ingredient, A. westlandi.(3)

These unfortunate incidences of nephropathy occurred because there was poor handling of Chinese herbs. In this case, the prescribed herb was S. tetrandra, but was incorrectly substituted with A. westlandi. These are two different herbs with distinct physical appearances and laboratory presentations. Aristolochia westlandii root is round, 8-15 cm in length, and 1.5-4.5 cm in diameter. The root has a thick and rough outer layer that is greyish-brown in color. (See photo.) In contrast, S. tetrandra root is round or cylindrical, 3-5 cm in length, and 3.5-5 cm in diameter. The outer layer of the root is dirt-brown in color with numerous pores.(4)

In August 7, 1999, The Lancet reported two additional cases of end-stage renal failure associated with the use of Chinese herbal remedies. Case one was a 49-year-old white female who took a Chinese herbal remedy for her eczema for two years. After complaining of headache and hypertension, she was screened for renal function and was found to have acute renal failure. She began dialysis immediately and subsequently received a cadaveric renal transplant. Case two was a 57-year-old white woman who took a Chinese herbal remedy for her eczema for six years. After a six-month history of anorexia, lethargy, nausea, and weight loss, she was admitted to the hospital with end-stage renal failure. She began dialysis immediately and was reported to be on the waiting list for renal transplant. In both cases, A. manshuriensis Kom., was the common ingredient in the herbal remedies. The Lancet reported that the investigation for other potential causes of renal failure were negative.(5)

In this case, nephropathy occurred because there was a lack of proper botanical verification in the preparation of the herb-drug mixture, resulting in the inadvertent use of A. manshuriensis. According to the Pharmacopoeia of the People's Republic of China, the herb mu tong may be derived from the following species of plants: Clematis armandii Franch. (Ranunculaceae) (chuan mu tong), C. montana Buch.-Ham. Ex DC. (chuan mu tong), or A. manshuriensis.(6,7) Due to the toxicity associated with aristolochic acid in A. manshuriensis,(8) C. armandii or C. montana are now used as the preferred sources of mu tong.(9)

With respect to visual inspection, A. manshuriensis is long and round, approximately 100 cm in length and 1.5-3 cm in diameter. The outer layer is greyish-yellow or light brown in color. It has enlarged joints in between parts of the plant and a distinct camphor-like odor. In contrast, C. armandii or C. montana is long and round, 50-100 cm in length, and 2-3.5 cm in diameter. The outer layer is light to dark yellow/brown in color. It has no joints and no odor.(9)

PREVIOUS REPORTS OF KIDNEY PROBLEMS WITH ARISTOLOCHIA

Nephropathy associated with the use of A. westlandi and A. manshuriensis is not an isolated incident. It has been documented in China, Belgium and England. Proper precautions must be taken to avoid such inappropriate substitutions and the resulting adverse reactions. Correct identification of the herb is imperative for safe and effective use of the herbs. Physical inspection is the most commonly used method of identification. However, it is not 100 percent accurate or reliable. In the Belgian incident, an incorrect substitution was used. In the English incident, there was a lack of verification for the safest herb. Since mu tong is derived from herbs in the genera Clematis, Akebia (Lardizabalaceae), or Aristolochia, the "preferred source is one that is most effective and has least adverse side effects. Clematis is usually considered the "preferred source" and Aristolochia the least desirable. Therefore, it can be concluded that visual inspection is insufficient for correct iden tification as the macroscopic physical appearances of the herbs are often indistinguishable. Laboratory techniques such as high performance liquid chromatography, thin-layer chromatography, and liquid-column chromatography must be used to confirm qualitative and quantitative analyses of the various herbs' chemical profiles. Furthermore, such examinations must be performed on every batch of herbs: random examinations will not ensure the safety of all herbal preparations. It is the ethical and legal responsibility of the herbal manufacturer to establish the most stringent quality control measures to ensure the safety of herbal products, and it is the duty of practitioners to purchase and dispense herbs from manufacturers who meet such criteria. It should be noted that the Belgian formulation was a "standard preparation." The English formulations were herbal teas custom-made for the individual patients.

According to proper quality control measures and good manufacturing practices (GMPs), certificates of analysis should accompany all lots of S. tetrandra and C. armandii, as well as other herbs manufactured in the U.S. Certificates of analysis offers documentation on the safety and purity of the herbs. Items routinely examined include heavy metal content, bacterial content, purity and positive identity of the herb.(10)

There has been some misreporting of these incidents in the literature. According to an article(13) in an Australian herb school newsletter by Debbie Shaw, a pharmacist, research scientist, and Head of the Traditional Medicine Project with the Medical Toxicology Unit at Guy's and St. Thomas Hospital Trust in London, reporters have confused the matter by equating renal failure and renal biopsies with fatality. "This has resulted in inaccurate reports of 30 deaths in Belgium (and even two deaths in the recent UK incident) which have not been confirmed by the reporting doctors. Such misreporting causes unnecessary alarm amongst the patients and the public."(13) Shaw adds that due to some confusion as to the cocktail of conventional drugs that were administered in the Belgian incident, along with possible serotonin injections, "It seems most likely that an interaction between the herb and the combination of drugs used contributed to the extreme nephrotoxicity."(13) However, she poin ts out, subsequent reports of nephrotoxicity associated with A. fangchi Y.C. Wu ex L.D. Chow & S.M. Hwang, have been reported in Japan and Belgium with no association with simultaneous use of conventional drugs.(14,15) She states, "Despite the large number of recent cases, it has not been possible to identity whether there is a toxic dose of aristolochic acids, or if chronic use of low concentrations has a cumulative effect.(11) This is apart from the herb/drug interactions increasing toxicity."

REFERENCE

(1.) Depierreux M, Van-Damme B, Vanden-Houte K, Vanherweghem JL. Pathological aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis. 1994;24(2):172-180.

(2.) Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet. 1993;341:387-391.

(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.) Tai X, et al. Chinese Herbal Botany. Taiwan: Chiyeh Press; 1974.

(5.) Lord GM, Tagore R, Cook T. Gower P. Pusey CD. Nephropathy caused by Chinese herbs in the UK [letter]. Lancet. 1999;354:481-482, 494.

(6.) Tu G, ed. Pharmacopoeia of the People's Republic of China. Beijing; Guangdong Science and Technology Press: 1992. p. 16-17, 304-305.

(7.) Zheng HZ, Dong ZH, et al. Mu tong. Mod Study Chin Med. 1997 Oct;1:936:954

(8.) Zhejiang. J Chin Med. 1965;12:32.

(9.) Zheng HZ, Dong ZH, et al. Mod Study Chin Med. 1997 Oct;1:936-954.

(10.) Lotus Herbs, Inc. Certificate of analysis for Stephania tetrandra (han fang ji) Apr 9, 1998, and Clematis armandii (chuan mu tong) Jul 8, 1998.

(11.) Jackson L, Kofman S, Weiss A, Brodovsky A. Aristolochic acid (NSCO50413): phase 1 clinical study. Cancer Chemother Rep. 1964;42:35-37.

(12.) Abel G, Schimmer O. Induction of structural chromosome aberrations and sister chromatid exchanges in human lymphocytes in vitro by aristolochic acid. Hum Genet 1983;64(2):131-133.

(13.) Shaw D. Aristolochia implicated in kidney failure alert in UK. Herbal Doctor. 1999 Dec;2(3):3-4.

(14.) Ono T, M Eri, G Honda, et al. Valvular heart disease and Chinese-herb nephropathy. Lancet. 1998;351:991.

(15.) Vanherweghem JL, Cuykens JJ, Vandengbergh PH, et al. Valvular heart disease and Chinese-herb nephropathy [reply to letter]. Lancet. 1998;351:991.

Article copyright American Botanical Council.

~~~~~~~~

By John K. Chen