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Chinese Herb Nephropathy: Aristolochic Acid and Kidney Failure

Bieler CA, Stiborova M, Wiessler M, Cosyns JP, van Ypersele de Strihou C, Schmeiser HH.  32P-post-labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy.Carcinogenesis 1997 May;18(5):1063-7
Abstract:  Recently, we reported that aristolochic acid (AA) a naturally occurring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). Indeed, we identified the principal aristolochic acid-DNA adduct in the kidney of five such patients. We now extend these observations and demonstrate the presence of additional AA-DNA adducts by the 32P-post-labelling method not only in the kidneys, but also in a ureter obtained after renal transplantation. Using the nuclease P1 version of the assay not only the major DNA adduct of aristolochic acid, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), but also the minor adducts, 7-(deoxyguanosin-N2-yl)-aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)-aristolactam II (dA-AAII) were detected, and identified by cochromatographic analyses with TLC and HPLC. Quantitative analyses of six kidneys revealed relative adduct levels from 0.7 to 5.3/10(7) for dA-AAI, from 0.02 to 0.12/10(7) for dG-AAI and 0.06 to 0.24/ 10(7) nucleotides for dA-AAII. The detection of the dA-AAII adduct is consistent with the occurrence of aristolochic acid II (AAII) in the herb powder imported under the name of Stephania tetrandra and confirms that the patients had indeed ingested the natural mixture of AAI and AAII. 32P-post-labelling analyses of further biopsy samples of one patient showed the known adduct pattern of AA exposure not only in the kidney, but also in the ureter, whereas in skin and muscle tissue no adduct spots were detectable. In an attempt to explain the higher level of the dA-AAI adduct compared to the dG-AAI adduct level in renal tissue even 44 months after the end of regimen, the persistence of these two purine adducts was investigated in the kidney of rats given a single oral dose of pure AAI. In contrast to the dG-AAI adduct, the dA-AAI adduct exhibited a lifelong persistence in the kidney of rats. Our data demonstrate that AA forms DNA adducts in human tissue by the same activation mechanism(s) reported from animal studies. Thus, the carcinogenic/mutagenic activity of AA observed in animals could also be responsible for the urothelial cancers observed in two of the CHN patients.


 
 

Cosyns JP, Jadoul M, Squifflet JP, De Plaen JF, Ferluga D, van Ypersele de Strihou C.  Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994 Jun;45(6):1680-8
Abstract:  Rapidly progressive interstitial renal fibrosis has recently been reported in young women who have been on a slimming regimen including Chinese herbs. We examined four nephroureterectomies performed in three patients prior to or at the time of transplantation to determine the nature and topography of the kidney and urinary tract lesions in Chinese herbs nephropathy (CHN). Extensive, hypocellular, interstitial sclerosis, tubular atrophy and global sclerosis of glomeruli decreasing from the outer to the inner cortex, including the columns of Bertin, were observed in the four kidney specimens, together with severe fibromucoid to fibrous intimal thickening, mainly of interlobular arteries, normal or collapsed residual glomeruli, and mild to moderate atypia and atypical hyperplasia of the urothelium. In addition, bilateral pelvi-ureteric sclerosis was observed in one case. With the exception of the latter, these lesions are very similar to those described in Balkan endemic nephropathy (BEN). The clinical presentation of the patients was also similar to that observed in BEN: normal blood pressure, aseptic leukocyturia, low grade low molecular weight proteinuria, early and severe anemia. In conclusion, on morphological and clinical grounds, CHN appears similar to BEN. A common etiologic agent, aristolochic acid, is suspected. The known carcinogenic potential of this compound, taken together with our finding of multiple foci of cellular atypia of the urothelium suggest that CHN patients should undergo a regular follow-up for urothelial malignancy.
 
 

Cosyns JP, Jadoul M, Squifflet JP, Wese FX, van Ypersele de Strihou C.  Urothelial lesions in Chinese-herb nephropathy.Am J Kidney Dis 1999 Jun;33(6):1011-7
Abstract:  Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

Comments:

    Comment in: Am J Kidney Dis 1999 Jun;33(6):1171-3
 
 
 

Cosyns JP, Goebbels RM, Liberton V, Schmeiser HH, Bieler CA, Bernard AM.  Carcinoma in the forestomach but no interstitial nephropathy in rats.  Arch Toxicol 1998 Nov;72(11):738-43
Abstract:  Chinese herbs nephropathy (CHN), a rapidly progressive interstitial fibrosis of the kidney, has been described in approximately 100 young Belgian women who had followed a
slimming regimen containing some Chinese herbs. In 4 patients multifocal transitional cell
carcinomas (TCC) were observed. Aristolochic acid (AA), suspected as the causal factor of
CHN, is a well known carcinogen but its ability to induce fibrosis has never been
demonstrated. The objective of this study was to evaluate the latter using doses of AA,
durations of intoxication and delays of sacrifice known to yield tumours in rats. We also
tested the hypothesis that a possible fibrogenic role of AA was enhanced by the other
components of the slimming regimen. Male and female rats were treated orally with 10 mg
isolated AA/kg per day for 5 days/week, or with approximately 0.15 mg AA/ kg per day 5
days/week contained in the herbal powder together with the other components prescribed in
the slimming pills for 3 months. The animals were killed respectively 3 and 11 months
later. At sacrifice, animals in both groups had developed the expected tumours but not
fibrosis of the renal interstitium. Whether the fibrotic response observed in man is due to
species and/or strain related differences in the response to AA or to other factors, remains to
be determined. Interestingly, despite the addition of fenfluramine and diethylpropion, two
drugs incriminated in the development of valvular heart disease, no cardiac abnormalities
were observed.
 
 

Levi M, Guchelaar HJ, Woerdenbag HJ, Zhu YP.  Acute hepatitis in a patient using a Chinese herbal tea--a case report.Pharm World Sci 1998 Feb;20(1):43-4
Abstract:  A case is presented of reversible acute hepatitis in a patient using a Chinese herbal tea. Upon identification of the tea mixture Aristolochia species, including A. debilis, which contains the highly toxic aristolochic acid, could be identified. We conclude that the acute hepatitis as described in this patient is most likely to be caused by (one of) the active ingredients of the Chinese herbal tea. Furthermore, this case illustrates that so-called natural products can cause unexpected severe adverse reactions.
 
 

Lord GM, Tagore R, Cook T, Gower P, Pusey CD. Nephropathy caused by Chinese herbs in the UK.Lancet 1999 Aug 7;354(9177):481-2
Abstract:  The use of Chinese herbal remedies is increasing in the UK. We report the presence of a nephrotoxic compound in herb samples, which led to end-stage renal failure in two patients. We suggest that use of these products is regulated more tightly.

Publication Types:

  • Letter

Mengs U.  Tumour induction in mice following exposure to aristolochic acid. Arch Toxicol 1988;61(6):504-5
Abstract:  After treatment for 3 weeks with aristolochic acid (AA) in daily doses of 5.0 mg/kg mice were kept under observation for approximately 1 year. During this period papillomatous changes occurred in the forestomach. At a later stage, squamous cell carcinomas were observed in all the animals. In one case, an adenocarcinoma was found in the glandular stomach. In addition, malignant lymphomas were found, as well as adenomas of the kidneys, carcinomas of the lungs, and haemangiomas of the uteri.
 
 

Mengs U.  Acute toxicity of aristolochic acid in rodents.Arch Toxicol 1987 Feb;59(5):328-31
Abstract:  The acute toxic effects of aristolochic acid (AA) were tested in rats and mice of both sexes. Oral or intravenous administration in high doses was followed by death from acute renal failure within 15 days. Histologically, the predominant features were severe necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, followed by hyperplasia and hyperkeratosis of the squamous epithelium. The LD50 ranged from 56 to 203 mg/kg orally or 38 to 83 mg/kg intravenously, depending on species and sex.
 
 

Sekita S, Kamakura H, Yasuda I, Hamano T, Satake M.  Aristolochic acids in herbal medicines.  Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku 1998;(116):195-6
Abstract:  Aristolochic acids are nitrophenanthrenes with a carboxylic acid fanction which have been found only among the Aristolochiaceae. In 1993, rapidly progressive interstitial renal
fibrosis has been reported in women have been on a slimming regimen including Chinese
herbal medicines in Belgium. In Japan, at the Kansai district, several cases of Chinese
herbs nephropathy have been reported quite recently. In both cases, aristolochic acids was
detected in the Chinese herbal medicines taken by the patients. We have Asiasarum Root, a
species of Aristolochiaceae, in Japanese Pharmacopoeia. Therefore, we quantitatively
analysed aristolochic acids in these herbal medicines and related plants.
 
 

Stengel B, Jones E.  End-stage renal insufficiency associated with Chinese herbal consumption in France.Nephrologie 1998;19(1):15-20
Abstract:  In May 1994 in Toulouse, there were two cases of end-stage renal failure (ESRF) related to Chinese herbs similar to those incriminated in the case series reported in Belgium in 1992-93, they led to an epidemiologic investigation aimed at evaluating the risk linked to these plants in France. Studies carried out by the Pharmacy Inspection showed that powders labelled Stephania Tetrandra, but consisting instead of Aristolochia Fangji and containing aristolochic acid, were sold in France between 1989 and May 1994. A systematic attempt to ascertain cases of ESRF associated with ingesting Chinese herbs was carried out by analysing data from the ERA-EDTA Registry of ESRF as well as from the French adverse drug reaction monitoring system. Registry data showed no significant increase over previous years in the number of new ESRF cases caused by tubulo-interstitial nephritis (TIN) between 1990 and 1993. In eight regions of France, the files of 85 ESRF cases were examined, and all patients whose nephropathy began after 1989 were interviewed using a very detailed questionnaire. No association with Chinese herb use was found in any of these cases. In 1996, two new ESRF cases were reported in Nice; the regional adverse drug reaction monitoring center considered the relationship with Aristolochia Fangji to be as possible (I2) for one case and dubious (I1) for the other. Despite a lack of sensitivity of the methods used to detect cases, it seems clear that no phenomenon as extensive as that observed in Belgium occurred in France, although the same drugs prescribed at the same doses have been widely distributed in our country. A possible explantation for the difference in the number of cases in Belgium and France is that of an unrecognised factor, promoting the toxicity of aristolochic acid or peculiar to the Belgian clinic and causative. The precautionary principle led the authorities to ban Stephania Tetrandra and Aristolochia Fangji from the market permanently.
 
 

Stiborova M, Frei E, Breuer A, Bieler CA, Schmeiser HH.  Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy.Exp Toxicol Pathol 1999 Jul;51(4-5):421-7
Abstract:  Aristolochic acid (AA) a naturally occuring nephrotoxin and carcinogen is implicated in a unique type of renal fibrosis, designated Chinese herbs nephropathy (CHN). We identified AA-specific DNA adducts in kidneys and in a ureter obtained from CHN patients after renal transplantation. AA is a plant extract of aristolochia species containing AA I as the major component. Aristolactams are the principal detoxication metabolites of AA, which were detected in urine and faeces from animals and humans. They are activated by cytochrome P450 (P450) and peroxidase to form DNA adducts. Using the 32P-postlabelling assay we investigated the formation of DNA adducts by aristolactam I in these two activation systems. A combination of two independent chromatographic systems (ion-exchange chromatography TLC and reversed-phase HPLC) with reference compounds was used for the identification of adducts. Aristolactam I activated by peroxidase led to the formation of several adducts. Two major adducts were identical to adducts previously observed in vivo. 7-(deoxyguanosin-N2-yl)aristolactam I (dG-AAI) and 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI) were formed in DNA during the peroxidase-mediated one-electron oxidation of aristolactam I. Aristolactam I activated by P450 led to one major adduct and four minor ones. Beside the principal AA-DNA adducts identified recently in the ureter of one patient with CHN, an additional minor adduct was detected, which was found to have indistinguishable chromatographic properties on TLC and HPLC from the major adduct formed from aristolactam I by P450 activation. Thus, this minor AA-adduct might be evolved from the AAI detoxication metabolite (aristolactam I) by P450 activation. These results indicate a potential carcinogenic effect of aristolactam I in humans.
 
 

Tanaka A, Nishida R, Sawai K, Nagae T, Shinkai S, Ishikawa M, Maeda K, Murata M, Seta K, Okuda J, Yoshida T, Sugawara A, Kuwahara T.  Traditional remedy-induced Chinese herbs nephropathy showing rapid deterioration of renal function. Nippon Jinzo Gakkai Shi 1997 Dec;39(8):794-7
Abstract:  A 19-year-old female was referred to our hospital for azotemia and anemia. She had been taking a health food for atopic dermatitis for about three years. Urinalysis showed proteinuria, glycosuria and microscopic hematuria. Generalized aminoaciduria was observed. Moreover, severe anemia, azotemia, hypokalemia and hypophosphatemia were also observed. Renal biopsy specimen disclosed hypocellular interstitial fibrosis and degeneration of the proximal tubular epithelial cells. No remarkable changes were observed in the glomeruli. Aristolochic acid was detected in the health food. From these findings, she was diagnosed as having Chinese herbs nephropathy (CHN). Although consumption of the food intake was stopped, her renal function deteriorated rapidly. Previously, we reported that certain kinds of Chinese herbal drugs contain aristolochic acid and that the drugs should be prohibited if aristolochic acid is identified. However, we experienced a patient of CHN arising from traditional remedy, which was not proved to be safe. It should be awared that health foods may contain aristolochic acid.
 
 

Tanaka A, Shinkai S, Kasuno K, Maeda K, Murata M, Seta K, Okuda J, Sugawara A, Yoshida T, Nishida R, Kuwahara T.  Chinese herbs nephropathy in the Kansai area: a warning report. Nippon Jinzo Gakkai Shi 1997 May;39(4):438-40
Abstract:  In 1993, Vanherweghem and his associates reported cases of rapidly progressive renal interstitial fibrosis in young women who were administered a slimming regimen including Chinese herbs. Subsequently, similar cases have been reported. In Japan, especially in the Kansai area, several cases of Chinese herbs nephropathy have already been reported. We experienced a patient suffering from Chinese herbs nephropathy (CHN), and further detected aristolochic acids from the Chinese herbs taken by the patient. Aristolochic acids are known to be causative agents of CHN. The danger of CHN should be noted as soon as possible and drugs containing aristolochic acids should be prohibited.
 
 

Vanherweghem JL. A new form of nephropathy secondary to the absorption of Chinese herbs Bull Mem Acad R Med Belg 1994;149(1-2):128-140
Abstract: An outbreak of rapidly progressive renal failure was observed in Belgium in 1992-1993 and was related to a slimming regimen involving chinese herbs, namely Stephania tetrandra and Magnolia officinalis. Seventy one cases were registered on january 1994, 35 of whom being on renal replacement therapy. Renal failure has been progressing in most of the cases despite the withdrawal of the exposure to the chinese herbs. Renal biopsies showed an extensive interstitial fibrosis with loss of tubes, predominantly in the outer cortex. Chemical analyses of the chinese herbs powdered extracts delivered in Belgium demonstrated a misidentification between Stephania tetrandra and another chinese herb, Aristolochia Fang-chi, potentially nephrotoxic. These observations indicate the need of intensive search of nephrotoxins in cases of interstitial nephritis of unknown origin. Also, they underline the necessity of the introduction of measures allowing the control of correct identification of herbs preparations.
 
 

Vanherweghem LJ.  Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium.J Altern Complement Med 1998 Spring;4(1):9-13
Abstract:  At least 100 cases of extensive interstitial fibrosis of the kidneys were observed in Belgium in women who had followed a weight-loss regimen that included the use of Chinese herbs. The possible relation between the renal disease and these Chinese herbs was investigated. It was shown that the prescribed Chinese herb called Stephania tetrandra was, in fact, inadvertently replaced by another Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in Belgium and in France. The development of renal disease in about 100 patients exposed to the so-called Stephania tetrandra stresses the need for more stringent control of herbal medicine.

Comments:

  • Comment in: J Altern Complement Med 1998 Spring;4(1):15-6
  • Comment in: J Altern Complement Med 1998 Summer;4(2):131-2
 
 

Violon C.  Belgian (Chinese herb) nephropathy: why?J Pharm Belg 1997 Jan-Feb;52(1):7-27
Abstract:  During the last years several patients with renal failure were admitted in Brussels hospitals. The progressive interstitial fibrosis with tubular atrophy seen in these patients has been ascribed to the slimming therapy preceding the pathology. The nephropathy was remarkable with regard to its extensive fibrotic process and the rapidity of its evolution. The ingestion of Aristolochia fangchi instead of the prescribed Stephania tetrandra, one of the components of the slimming therapy, was put forward as hypothesis for the etiology of the nephropathies in the literature. Questions however remain unanswered: Why have certain persons, among thousands similarly treated including ingestion of Aristolochic acids, not withstood the treatment? Why is there no correlation between the length of treatment and the occurrence nor the degree of illness? Last but not least: Is it in the actual conditions possible to be confident again in slimming treatments as the concerned one? We made an overview of the pharmacological action and possible (nephro) toxicity of the known components of the concerned therapy. Concerning the Chinese plants we have described and commented on the procedures for quality control actually at disposal and the difficulties in differentiation between resembling species and possible substitute herbs. We have described largely the traditional and medicinal use of the involved Chinese plants as to evaluate their implication in the nephrotoxicity. The elements of the therapy possibly relevant in the etiology of the disease are mentioned. The overview shows that different elements of the therapy are hazardous. Attention is caught to the danger of the use of (Chinese) herbs of unknown origin when nor the indications nor the form of preparation--in this case decoctions--are respected and when the quality cannot be assured, due to lack of (official) operating procedures. Medicinal plants as those implied contain secondary metabolites (bis)-benzylisoquinoline-alkaloids, dihydroxy-diallyl-biphenyls, aristolochic acids) with strong pharmacological (and possibly toxic) actions. Attention is caught to the danger of alternative therapies as mesotherapy. Products are injected which are not proved safe for this administration way. The administration during long periods of cocktails with anorectics (fenfluramine and diethylpropion) in association with a diuretic, a tranquilizer, plants with laxative and atropinergic action are alike to be at the origin of susceptibility in the excretion system. Under these circumstances exposure to any toxic product might cause renal failure. Several years have passed after the scientific reports of the first nephropathy cases in Belgium. We are afraid that prohibiting (temporarily) three Chinese herbs (Stephania tetrandra, Aristolochia fangchi and Magnolia officinalis) does not provide enough safety in order to assume responsibilities for common health care. Keeping in mind that these treatments were not meant to cure any disease but only for slimming, we ask Belgian authorities to regulate strictly the use of (Chinese) herbal medicines, the products and practices in alternative practices as mesotherapy and cocktail-treatments.

 

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