Nephrology Dialysis Transplantation

NDT Advance Access originally published online on April 3, 2007
Nephrology Dialysis Transplantation 2007 22(6):1512-1517; doi:10.1093/ndt/gfm167

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For patients taking herbal therapy—lessons from aristolochic acid nephropathy

Joëlle L. Nortier and Jean-Louis Vanherweghem

Nephrology, Dialysis and Renal Transplantation, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium

Correspondence and offprint requests to: Joëlle L. Nortier, MD, PhD, Nephrology, Dialysis and Renal Transplantation, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium. Email: jnortier{at}ulb.ac.be

Keywords: Aristolochia; complementary and alternative medicine; herbal remedies; toxic nephropathy

	Introduction

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
Herbal medicines are but one component of complementary and alternative medicine (CAM), which includes acupuncture, chiropractic manipulation, meditation, reflexology, homeopathy, folk medicine and other approaches [1]. The term ‘CAM’ has been defined by Eisenberg and colleagues in the nineties as ‘those interventions neither taught widely at US medical schools nor generally available in US hospitals’ [2]. The increasing popularity of these therapies is attested by US national surveys showing an increase of 25% in the overall prevalence of use between 1990 and 1997. The Centers for Disease Control and Prevention reported that 29% of the adults in the US used CAM in 1999, with 10% ingesting herbal medicines [1]. In 2001, 17.8 billion USD were spent on dietary supplements, and 4.2 billion USD of this were for herbs and other botanical remedies [3]. Herbal medicine is also a big business in Europe. In 2003, European countries spent almost 5 billion USD on over-the-counter herbal medicines (at manufacturer prices to wholesalers) [4]. In some developing countries, these types of medicine have been supported by the World Health Organization, and received equal status with Western medicines by the local governments [5].

Popular perception is usually that botanical products used as folk or traditional remedies are inherently safe. However, many substances of vegetal origin used as herbal remedies can be nephrotoxic [6]. According to Huxtable [7], the origins of serious side-effects may be classified into three categories: first, the plant was correctly identified but its toxicity is unknown or underestimated; second, there has been an accidental or deliberate modification of the herb preparation by the addition of well-known, potentially toxic substances; and third, the herb was incorrectly identified or substituted by another more toxic compound. Thus, the clinical entity initially called Chinese-herb nephropathy (CHN), more accurately replaced by the title aristolochic acid nephropathy (AAN), is a dramatic example of mixed categories: in Belgian cases, the expected herb had been substituted by another more toxic agent. Furthermore, the fact that interchangeability of one herb by another is normal and acceptable in many traditional Chinese medicine (TCM) pharmacopoeias makes it likely that the toxicity of Aristolochia sp. itself is currently underestimated in large parts of the world [8]. In this review, we will use our experiences with AAN to illustrate the devastating consequences of inappropriate use of herbal medicine.

	Multicultural aspects of Aristolochia species

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
The genus Aristolochia (family Aristolochiaceae) contains several species that are often found in TCM; e.g. Aristolochia fangchi, A. manshuriensis, A. contorta and A. debilis. They differ in the shapes of their leaves but have similar roots, which have a typical tree trunk structure when cut transversally [9]. Each medicinal part of the plant (root, stem, fruit, herb) has a distinct Chinese name. The family name Aristolochiaceae takes its origin from the Greek word ‘Aoo’, meaning ‘correct delivery’. The roots of A. indica have been used in Indian folk medicine as an abortifacient [10,11]. In TCM, various therapeutic purposes have been attributed to Aristolochia sp. Dried roots, stems or leaves by themselves or as a part of complex prescriptions have been proposed as remedies for asthma, coughs, haemorrhoids, arthralgia, oedema, headache, abdominal pain, snake and insect bites, ulcers and urinary tract infections [9]. Its use in the folk medicine of many European countries has been known for centuries. For example, A. clematis has been used to treat gastrointestinal and gallbladder colic. Powder from Aristolochia sp. was available in most medieval pharmacies, like that of the Hôtel Dieu in the Baugé castle in France (Figure 1A). Catherine de Médicis's study in the famous Chenonceau castle, known as ‘the green room’, contains the Brussels tapestry from the 16th century called ‘Aristolochia Tapestry’, reflecting the European taste for exotism (Figure 1B).

View larger version (125K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1. (A) The Hôtel Dieu pharmacy of the Baugé castle in France is recognized as a historical monument and is open to the public. A collection of pots, boxes and folk remedies used during 16th and 17th centuries (deer horns, crayfish eyes, woodlouse powder) are exhibited. Paillat Baugé photograph. Courtesy of Mrs Reuze-Laverdure. (B) The green cabinet, well-known as Catherine de Médicis's study in the Chenonceau castle (France), contains the Brussels ‘Aristolochia Tapestry’. Courtesy of Mr Galand. (C) Typical slimming pill ingested by Belgian patients, in which AAs contained in pulverized root (cross-section shown) extracts of A. fangchi (Guang Fang Ji) were detected. They were used to replace the expected tetrandrine contained in the so-called prescribed S. tetrandra (Han Fang Ji).

 

	Historical discovery of aristolochic acid nephropathy

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
In the early 1992, cases of renal failure rapidly progressing to end-stage renal disease (ESRD) were reported in Belgium, which were associated with daily intake of slimming pills which included root extracts from Chinese herbs (Stephania tetrandra and Magnolia officinalis) (Figure 1C) [12]. Very soon, the inadvertent replacement of S. tetrandra by A. fangchi was suspected, since TCM classifies S. tetrandra (Pin Yin name: Han Fang Ji) and A. fangchi (Pin Yin name: Guang Fang Ji) within the same therapeutic ‘Fang Ji’ family. Herbal ingredients are traded using their common Pin Yin name. This initial hypothesis was confirmed in 1994 by phytochemical analyses of the so-called Stephania batches, leading to the detection of aristolochic acids (AA), the main compounds of the Aristolochia sp. [13]. Moreover, renal tissue samples from patients exposed to the so-called S. tetrandra contained specific AA–DNA adducts. Aristolactams, activated metabolites formed by AA nitroreduction, are actually able to form DNA adducts through covalent binding sites with adenosine and guanosine [14,15]. Finally, this new renal disease, initially called CHN and more appropriately later AAN, has been experimentally reproduced by AA administration to laboratory animals (see section ‘Experimental AAN’).

	The wide clinical spectrum of aristolochic acid nephropathy

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
In initial reports, AAN had been described as a paucisymptomatic chronic renal failure without proteinuria (negative dipstick) or alteration of the urinary sediment [16,17]. Severe anaemia was a predominant sign in some cases [18]. Macroscopically, the kidneys were shrunk (Figure 2A) and asymmetry was noted in about half of the cases [16]. Microscopically, an extensive interstitial paucicellular fibrosis was observed in the superficial cortex, mainly composed of proximal tubules, and this progressed towards the deep cortex [19,20] (Figure 2B). This destructive process resulted in severe atrophy of the proximal tubular population, although the glomeruli remained intact at least in the beginning of the disease. Measurements of urinary levels of neutral endopeptidase, an ectoenzyme of the proximal tubule brush border, and low molecular weight proteins, such as Clara cell protein, in patients with distinct degrees of renal failure confirmed the progressive structural and functional impairment of this part of the nephron, and these levels were found to correlate with the severity of the disease [21,22].

View larger version (47K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2. (A) Compared with a normal kidney (left), severe renal atrophy with degeneration of the cortex from a 47-year-old woman presenting with ESRD in 1992 after a 2 year maximum intake period of the so-called S. tetrandra preparations (estimated cumulated dose of 374 g). (B) Representative renal biopsy performed in a 49-year-old woman admitted in 1993 with Chronic Kidney Disease (CKD) stage 4 (creatinine clearance reduced to 37 ml/min) 1 year after having ingested an estimated cumulated dose of Aristolochia of 186 g during 13 months, showing extensive interstitial fibrosis, some inflammatory infiltrating cells and intact glomeruli. Masson's trichrome (original magnification 100x).

 
Some cases presented with a Fanconi syndrome, reinforcing the hypothesis that the proximal tubule was a preferential target for AA (cases reviewed in [17] and [23]). Other unusual clinical presentations have been described, such as acute renal failure developing in primary renal disease from another origin [24], as well as bilateral hydronephrosis combined with periureteral fibrosis [25,26].

The clinical course of AAN has been related to the intensity of AA exposure. For example, we found a positive correlation between the estimated total dose of Aristolochia sp. ingested by our patients and the severity of renal dysfunction, as reflected by the slope of the inverse of serum creatinine [27]. In our cohort, patients who further developed ESRD had ingested a mean total dose of 192 ± 13.1 g of Aristolochia during a mean time period of 13.6 ± 0.8 months, whereas those who developed chronic renal failure had ingested a significantly lower amount (138 ± 16.3 g, P = 0.0046) during an equivalent mean time period (11.0 ± 1.2 months, P = 0.07).

Up to now, therapeutic strategies have been mainly conservative when renal insufficiency is detected. In our hands, angiotensin-converting enzyme inhibitors did not modify the evolution of the renal disease (personal data). Following the observation that inflammatory cells had infiltrated the interstitium in renal biopsy specimens, a pilot study was performed with corticosteroids and showed a slowing of renal failure progression in several patients, suggesting an immunological involvement in the still unknown mechanisms linking AA intoxication to renal fibrosis [28].

	AAN complicated by urothelial carcinoma

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
Moderate atypia and atypical hyperplasia of the urothelium were first described in four specimens from nephroureterectomies performed in three AAN patients prior to or at the time of transplantation [19]. Three cases of urinary tract cancer were further reported: in the first one, bladder involvement (papillary tumours) was described in an AAN patient that required renal transplantation [29]; the second case presented with haematuria secondary to a papillary transitional cell carcinoma of the right pelvis [30]; and the third case developed a hydronephrosis of the left native kidney after a successful transplantation for terminal AAN diagnosed in the UK. The specimens from the nephroureterectomy showed a multifocal transitional cell carcinoma of the ureter [31]. Therefore, at the end of 1997, we informed our AAN patients having ESRD who were treated by dialysis or transplantation about the risk of developing urothelial carcinoma and suggested the prophylactic removal of their native kidneys and ureters. Among 39 patients who agreed to undergo surgery, a dramatically high prevalence of upper urinary tract cancer (46%) was reported, which included 17 cases of carcinoma of the ureter, renal pelvis, or both, and one papillary bladder tumour [15]. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia and two had normal urothelium. Cosyns et al. [32] had also reported a high prevalence with four cases out of 10 developing urinary tract carcinoma. In renal transplanted patients, the literature usually reports a prevalence of about 5% for this type of cancer [33,34]. All of the analysed renal tissue samples from our patients contained AA-related DNA adducts. There were no significant differences in the mean levels of the major DNA adduct, 7-(deoxyadenosine-N⁶-yl)-aristolactam I DNA adduct, in renal tissue samples between patients in whom urothelial carcinoma had developed and those in whom it had not developed. The cumulative dose of ingested Aristolochia was a significant risk factor for urothelial carcinoma, with total doses of >200 g associated with a higher risk of urothelial carcinoma. Finally, only four of the 25 tissue samples analysed for ochratoxin A-related DNA adducts were weakly positive (and they were close to the background level of the assay), indicating that ochratoxin A did not play a key role in AAN. This mycotoxin has been involved in the aetiology of Balkan endemic nephropathy, a chronic progressive renal interstitial disease exhibiting similarities to AAN-induced pathology in terms of histological lesions and urinary tract cancer complications [19,35].

Urothelial cancer seemed to be a late complication of CHN since all of the cases had been detected in ESRD patients. However, we reported a case with cervical adenopathy secondary to metastatic carcinoma of the left pelvic cavity in a woman taking Chinese herbal medicine containing AA but having only mild renal failure, suggesting a possible dissociation between carcinogenicity and nephrotoxicity [36]. Along the same line, inaugural macroscopic haematuria was also reported in a 30-year-old Chinese man who had ingested for several years Longdan Xieganwan, a Chinese product containing A. manshuriensis. Urothelial carcinoma of the bladder was found as well as an increased serum creatinine level. Renal biopsy showed interstitial fibrosis consistent with AAN and a progressively deteriorating renal failure that reached ESRD after 2 years [37].

	Tubulotoxicity and carcinogenicity of Aristolochia sp.

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
Aristolochic acids, the main compounds of Aristolochia sp., are nitrophenanthrene derivatives known for their potent carcinogenic action in rodents [38] as well as for their mutagenic properties in bacterial [39] and mammalian models [40]. In vitro studies examining specific AA-DNA adduct formation showed that cytochrome P4501A1 and 1A2 as well as prostaglandin H synthetase were involved in the metabolic activation caused by AA [41,42]. These observations could explain interindividual variations in the susceptibility to AA toxicity as well as the preferential localization in the kidney and urinary tract. Carcinogenicity of AA-DNA adducts has also been related to the mutation in codon 61 of the proto-oncogen Has-ras [43] as well as to a mutation of p53 [32]. Thus, specific AA-DNA adducts are recognized not only as markers of prior exposure to AA, but are also involved in the tumourigenesis process, as recently detailed in a comprehensive pathophysiological review [44].

Finally, the tubulotoxicity of AA was assessed in vitro in an opossum kidney (OK) cell line. Exposure of cultured cells to AA induced a significant impairment in the receptor-mediated endocytosis process of albumin and ß₂-microglobulin, a decrease in megalin expression and the formation of specific DNA adducts [45]. In vivo demonstration of early structural and functional impairments of the S3 segment of proximal tubules was provided by studying the rat model of AAN [46]. Another in vitro study using LLC-PK1 cells underlined the critical role of nitro (–NO2) and methoxy (–OCH3) groups in the cytotoxic actions caused by AA I, the predominant constituent of Aristolochia sp., and by its structural analogues. AA I was the most active, whereas its corresponding nitroreduction products (aristolactams) were devoid of high toxicity [47].

	Experimental AAN

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
Despite some evidence in humans, there was little experimental indication that AA itself could induce chronic renal failure via progressive interstitial fibrosis. Initial attempts to experimentally reproduce AAN failed [48]. In contrast, rabbits receiving intraperitoneal injections of 0.1 mg/kg AA (5 d/w, for 17–21 months) developed severe hypocellular interstitial fibrosis, urothelial atypias and tumours of the urinary tract in three cases [49]. In the salt-depleted Wistar rat model, subcutaneous daily administration of 10 mg/kg AA induced renal failure after 35 days of treatment, with interstitial fibrosis as well as papillary urothelial carcinoma of the pelvis in some of the rats [50]. Using this model, we found that other potential nephrotoxic substances (dexfenfluramine, diuretics), also contained in the weight-reducing pills, did not enhance the renal toxicity of AA [51]. Interestingly, inhibition of the renin–angiotensin system did not prevent the development of renal lesions, suggesting that physiopathological mechanisms leading to renal fibrosis may be largely independent of angiotensin II, which is in contrast to other animal models [52].

	Conclusion

Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 
Chronic exposure to Aristolochia toxins is associated with the development of renal interstitial fibrosis (AAN) and urinary tract carcinoma. Cases of AAN have been reported in France, Spain, Japan, UK and Taiwan [17,23,44]. Health professionals should be aware that in traditional herbal medicine, TCM, Japanese kampo and Ayurvedic medicine, Aristolochia sp. are still in use and regularly replace S. tetrandra, Akebia, Asarum, Clematis sp. and Cocculus sp. in herbal remedies. Despite strong warnings from the Food and Drug Administration (FDA) in 2001 [53] and the classification of Aristolochia sp. containing products as human carcinogens in 2002 by IARC [9], a recent report showed that many compounds containing AA or suspected to contain AA are currently sold on US web sites [54]. When faced with a renal disease or a urothelial carcinoma of ‘unknown origin’, nephrologists and urologists should extend their clinical inquiry to the frequent use of ‘non-western’ medicine.

These observations support the view that extracts of herbal preparations, often considered without any risk to the public, should be submitted to quality controls which are as strict as for any conventional drug. In the US, the Dietary Supplement and Health Education Act (DSHEA) broadly defined herbs and other botanicals as ‘dietary supplements’, thus altering the way by which claims about effectiveness and safety of these products could be evaluated [3]. In 2004, the European Community adopted a directive creating a simplified registration procedure for all traditional herbal medicines. By introducing a list of unacceptable herbs and mandatory adverse event reporting, the European legislation went beyond the new rules for Good Manufacturing Practice proposed in 2003 by the FDA to improve the quality of dietary supplements. Nevertheless, some caveats persist, and these include the focus on industrial preparations but not on crude herbal ingredients used in locally compounded medicines, the new directive allowing non-medicinal herbal products to be regulated under legislation covering foods, the tool for safety assessment that is still based on traditional experience, which is obviously not always reliable for the detection of rare reactions, and finally the new European directive that continues to accept different standards for alternative types of medicine, since the scientific proof of efficacy required for pharmaceutical medicines is no longer needed for herbal medicines [4].

Lessons from AAN clearly show that there is an urgent need to protect the public from dangerous practices while permitting patient access to reasonably safe and effective therapies. The only way to achieve this is to submit all phytotherapy products to the same regulations as for any conventional drug [55].

Conflict of interest statement. None declared.

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Top Introduction Multicultural aspects of... Historical discovery of... The wide clinical spectrum... AAN complicated by urothelial... Tubulotoxicity and... Experimental AAN Conclusion References

 

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Received for publication: 13. 9.06
Accepted in revised form: 5. 3.07

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