To the Editor:

The patients described by Nortier et al. (June 8 issue) (1) took not only a Chinese herb but also dexfenfluramine, acetazolamide, amphetamines, theophylline, and deadly nightshade. (2,3) The confounding factor of drug interactions was not discussed in the article. More important, the smoking habits of these patients were not detailed, and the investigators did not look for the DNA adducts associated with dexfenfluramine and cigarette tar.

Shu Shum, M.D.
　　Northwest Texas Hospital
　　Amarillo, TX 79106

References

1. Nortier JL, Martinez M-CM, Schmeiser HH, et al. Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi). N Engl J Med 2000;342:1686-92.
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2. McIntyre M. Chinese herbs: risk, side effects, and poisoning: the case for objective reporting and analysis reveals serious misrepresentation. J Altern Complement Med 1998;4:15-6.
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3. Malak J. Chinese herb nephropathy is not a dexfenfluramine nephropathy but a serotonin nephropathy. J Altern Complement Med 1998;4:131-2.

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　　To the Editor:
　　Nortier and colleagues raise the possibility that aristolochic acid causes urothelial carcinoma in patients with Chinese-herb nephropathy. However, the mechanism for and possible treatment of this unusual type of nephropathy need to be further explored.

Aristolochic acid can cause apoptosis in a porcine renal-cell line (LLC-PK1) in a concentration-dependent manner, with significantly elevated intracellular calcium concentrations in the apoptotic cells. (1) These findings suggest that the elevation of the intracellular free calcium concentration is associated with the apoptosis of tubular cells in Chinese-herb nephropathy. Since both acetazolamide and fenfluramine, two ingredients in the Belgian weight-reducing pills, can alter intracellular calcium concentrations, it is possible that these two drugs play a part in the development of nephropathy and even in the development of carcinoma.

Weidong Lu, M.D.
　　New England School of Acupuncture
　　Watertown, MA 02472

Weining Lu, M.D.
　　Brigham and Women's Hospital
　　Boston, MA 02115

References

1. Gao RT, Zhang FL, Liu YX, Zheng DX, Li XM, Liu Y. Effects of the calcium antagonist on aristolochic acid I induced apoptosis in LLC-PK1 cells and intracellular Ca 2+. J Nephrol Dial Transplant 1999;8:6-9. (In Chinese.)

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　　To the Editor:
　　The outbreak of Chinese-herb nephropathy in Belgium is an example of serious misuse and abuse of medicinal herbs. The toxic effects are not caused by the ingestion of herbs as they are commonly consumed but by the consumption of a toxic product for an extended period of time as a result of human error and perhaps inadequate training of the practitioners. The original formula for dietary treatment should contain fang ji (Stephania tetrandra) and huo pu (Magnolia officinalis). But the formula used for a mean period of more than 12 months by the patients with renal nephropathy contained guang fang ji (Aristolochia fangchi), as proved by chemical analysis. It is indeed the aristolochic acid in guang fang ji that had renal toxicity.

It is clear from the Chinese National Pharmacopoeia that fang ji is the root of the S. tetrandra plant, whereas guang fang ji is from a totally different plant, A. fangchi. (1) Since fang ji does not have a renal toxic component, the tragedy would never have occurred if the correct herbs had been used in the Belgian dietary clinic.

Guang fang ji and related herbs have antiarthritis and diuretic effects and are often used together with other herbs to optimize efficacy and reduce toxicity. None of these herbs have been used in traditional Chinese medicine for weight control. They have a low level of toxicity and should be used with caution; they should never be used during pregnancy. The proper dose is 3 to 9 g of the decocted herb per day, and the herbs should be used for only a short period of time. The patient's renal function should also be monitored regularly. In the Belgian cases, the physicians apparently did not follow these guidelines of traditional medicine.

Yong Ming Li, M.D., Ph.D., D.C.H.
　　North Shore University Hospital
　　Manhasset, NY 11030

References

1. Chinese national pharmacopoeia: color atlas of Chinese herbs. Hong Kong, China: Wang Wen, 1991.

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　　The authors reply:
　　To the Editor:

Both Shum and Lu and Lu refer to possible drug interactions in the development of renal fibrosis and urothelial carcinoma. We agree that the pills ingested by the patients we described contained not only powdered extracts of A. fangchi but also anorectic drugs and acetazolamide. We acknowledged in our article the possibility that these drugs enhance the toxicity of aristolochia species. Although all 39 patients we described took pills containing Chinese herbs and fenfluramine, univariate analysis showed no statistically significant association between fenfluramine and cancer. Moreover, 12 of the patients had not received acetazolamide and 23 had not received dexfenfluramine, yet these patients had kidney disease and in some cases urinary tract carcinoma. We also searched for DNA adducts related to tobacco. They were present in only 4 of 12 smokers, whether or not urothelial carcinoma was present.

The mechanisms proposed by Lu and Lu are interesting but need to be investigated in vivo. In our experience, calcium-channel blockers do not slow the progression of renal failure in patients with Chinese-herb nephropathy. (1)

Li confirms the dangers of misidentification in herbal medicine and stresses that the practice of herbal medicine requires skill and experience. Interestingly, adverse renal effects of Chinese herbs have been reported in Japan (2) and in Taiwan, (3) where the herbs were used in accordance with the guidelines of traditional Chinese medicine but without control of the quality and conformity of the raw materials used in herbal remedies.

We therefore strongly believe that herbal substances should be subjected to the same stringent scrutiny and controls as common drugs before their release on the market.

Joelle L. Nortier, M.D., Ph.D.
　　Jean-Louis Vanherweghem, M.D., Ph.D.
　　Erasme University Hospital
　　B-1070 Brussels, Belgium

Heinz H. Schmeiser, Ph.D.
　　German Cancer Research Center
　　D-69120 Heidelberg, Germany

References

1. Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M. Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 1996;27:209-15.
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2. Tanaka A, Nishida R, Maeda K, Sugawara A, Kuwahara T. Chinese herb nephropathy in Japan presents adult-onset Fanconi syndrome: could different components of aristolochic acids cause a different type of Chinese herb nephropathy? Clin Nephrol 2000;53:301-6.
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3. Yang CS, Lin CH, Chang SH, Hsu HC. Rapidly progressive fibrosing interstitial nephritis associated with Chinese herbal drugs. Am J Kidney Dis 2000;35:313-8.
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(From The New England Journal of Medicine -- October 26, 2000 -- Vol. 343, No. 17)