Chapter 7 Aristolochic Acid Nephropathy: An Environmental and Iatrogenic Disease

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This chapter reviews the molecular and clinical toxicology of aristolochic acid (AA), nephrotoxic chemical carcinogen. Recently, AA, a principal component of all Aristolochia sp., is shown to be the toxin responsible for the clinical syndromes known as Chinese herb nephropathy (CHN) and endemic (Balkan) nephropathy (EN). The epidemiology and pathophysiology of CHN and EN are reviewed extensively and the association of these diseases with human cancer is the subject of several comprehensive reports. Both disorders are associated with a high incidence of urothelial (transitional cell) cancer and appear to constitute a single disease entity, designated aristolochic acid nephropathy (AAN). The dramatic revelation that AA is a powerful nephrotoxin and carcinogen for humans drew attention to the worldwide distribution and extensive use of Aristolochia sp. as herbal remedies. The subsequent reports described almost 200 patients outside of Belgium in whom chronic renal failure followed ingestion of Aristolochia herbs. In addition based on the traditional use of Aristolochia in herbal remedies, the chapter posits that AAN represents a long-overlooked iatrogenic disease and an international public health problem of considerable magnitude.

Introduction

The Aristolochiaceae family of herbaceous plants, specifically members of the genus Aristolochia, has been used for medicinal purposes for more than 2500 years [1]. Remarkably, the extensive materia medica describing the therapeutic use of Aristolochia rarely mentions its intrinsic toxicity. Recently, aristolochic acid (AA), a principal component of all Aristolochia sp., was shown to be the toxin responsible for the clinical syndromes known as Chinese herb nephropathy (CHN) and endemic (Balkan) nephropathy (EN). Both disorders are associated with a high incidence of urothelial (transitional cell) cancer and appear to constitute a single disease entity, designated aristolochic acid nephropathy (AAN).

The epidemiology and pathophysiology of CHN and EN have been reviewed extensively [[2], [3], [4], [5], [6], [7]] and the association of these diseases with human cancer is the subject of several comprehensive reports [[8], [9]]. Guided by the hypothesis that AA is the common etiologic agent in CHN and EN [[10], [11]], we review the molecular and clinical toxicology of this potent nephrotoxic chemical carcinogen. Additionally, based on the traditional use of Aristolochia in herbal remedies, we posit that AAN represents a long‐overlooked iatrogenic disease and an international public health problem of considerable magnitude [12].

Section snippets

Toxicity of Aristolochia

Toxicologists have long been aware of the toxic properties of Aristolochia sp. In 1825, while investigating the homeopathic principle that “like cures like,” Jörg performed experiments on himself and his colleagues, revealing the acute toxic properties of Aristolochia serpentaria [13]. Among the effects experienced after ingesting multiple doses of the root (2.5–7.5 gm, each dose estimated to contain ∼5 mg AA), were intense gastrointestinal discomfort and polyuria. Later, Orfila, the founder of

AA‐I and AA‐II

Aristolochia herbs contain a number of structurally related nitrophenanthrene carboxylic acids, principally aristolochic acid I (AA‐l) and aristolochic acid II (AA‐ll) [22]. Many of the studies discussed here utilize the naturally occurring mixture of AA‐l and AA‐ll, designated for purposes of this discussion as AA.

Chinese Herb Nephropathy

Between 1990 and 1992, ∼1800 otherwise healthy Belgian women inadvertently ingested Aristolochia fangchi in conjunction with their participation in a weight‐loss regimen. Several of these women developed rapidly progressive renal interstitial fibrosis leading to chronic renal failure [23]. Histopathologic examination revealed a corticomedullary gradient of interstitial fibrosis, and marked atrophy of proximal tubules with glomeruli generally being spared. Approximately 5% of women ingesting the

Endemic (Balkan) Nephropathy

EN is a chronic tubulointerstitial disease occurring in rural villages located near tributaries of the river Danube in Bosnia and Herzogovina, Bulgaria, Croatia, Romania, and Serbia. First described 50 years ago [[36], [37], [38], [39]], EN is estimated to affect at least 25,000 individuals in countries harboring this disease, while another 75,000 men and women residing in endemic regions are believed to be at risk [40]. Significant epidemiologic features of EN include its focal occurrence in

AAN = BEN = CHN

In the following section, we review critically the toxicology of AA, focusing on renal proximal tubules and urothelial cells, which are targeted by the toxin. In so doing, we integrate observations on the pathophysiology of CHN and EN with research on animal models of AAN and mechanistic studies of the molecular and cellular effects of AA (reviewed in [21]).

Dose–Toxicity Relationship

Estimates have been made of the amount of AA ingested by ∼100 Belgian women who developed end‐stage renal failure [[3], [55]] and by many of the ∼200 sporadic cases of CHN reported in the world literature (reviewed in [9]). Our analysis of the dose–toxicity relationship assumes that AA‐induced DNA damage in cells is cumulative and largely irreversible. Thus, 1800 Belgian women received a maximum of 0.025 mg/kg of AA over a period averaging 13 months, with 5% of this group developing end‐stage

Renal Histopathology

AAN is marked by progressive tubulointerstitial fibrosis resulting in ESRD. Comparison of patients with CHN and EN revealed a striking histopathologic feature, namely, a corticomedullary gradient of interstitial fibrosis present in both diseases [54]. This gradient, reported only in AAN and cadmium‐induced nephropathy [58] is even more pronounced in renal biopsies obtained prior to the development of ESRD.

New Zealand White rabbits treated over a period of 17–21 months with low doses of AA

Proximal Tubular Function

AAN is characterized by proximal tubule dysfunction, including persistent glycosuria, aminoaciduria, and low‐molecular weight (tubular) proteinuria (LMWP) [[3], [4]]. Normally, LMWP are filtered at the glomerulus, reabsorbed by endocytosis in the proximal tubule, and then catabolized. Proximal tubule damage interferes with this process; thus, the urinary LMWP/albumin ratio is strikingly elevated in patients with CHN and EN compared with patients with glomerular disease [63]. This parameter

Urothelial Cancer

The strong association between exposure to AA and the development of urothelial neoplasia was first recognized in Belgian women with CHN [[24], [68]]. Ultimately, 40–45% of this group developed multifocal high‐grade transitional cell carcinomas located primarily in the upper urinary tract [25]. Based on this observation, prophylactic bilateral nephroureterectomy is strongly recommended for CHN and EN patients requiring dialysis or renal transplantation.

UUC is prevalent among residents of

AL‐DNA Adducts

Both AA‐l and AA‐ll are subject to enzymatic nitroreduction in mammalian cells, generating active nitrenium intermediates (Figure 1) that react with the exocyclic amino groups of deoxyadenine and deoxyguanine bases of DNA (reviewed in [26]). Both AL‐l‐ and AL‐ll‐derived DNA adducts were detected in the renal cortex of patients with EN and/or UUC [50] and in persons ingesting botanical products containing AA (reviewed in [9]).

The level of AL‐DNA adducts in target tissues represents the

Mutational Signature of AAN

Mutational analysis of the p53 tumor suppressor gene in UUC tumors from patients residing in endemic villages revealed that the frequency of A:T → T:A mutations was 78% [50]. In contrast, A:T → T:A mutations occur infrequently in transitional cell carcinomas of the renal pelvis (0%), ureter (5%), and bladder (4.8%) in patients from nonendemic regions [79]. Importantly, the p53 mutation pattern in UUC associated with EN is consistent with the mutational spectra induced by AA‐I (or by a mixture

Genetic Considerations

Only 5% of the 1800 Belgian women exposed to similar amounts of AA developed AAN [3] and the reported prevalence of EN is 3–7% [5]. Similarly, various strains of mice exhibit differing susceptibilities to the toxic effects of AA [[59], [60]]. Thus, genetically determined interindividual variability may contribute to the risk of developing AAN and/or its associated UUC [85]. Rarely, however, does a single mutated gene result in a high absolute risk of an associated cancer or other disease. Thus,

AAN as an Iatrogenic Disease

The varied uses of Aristolochia (birthwort) have been traced from the fourth century BC to the eighteenth century AD, based on excerpts from the original literature [1]. The actual cumulative doses of Aristolochia employed in treating illness during the Greco‐Roman period were estimated by Scarborough who suggested that this early usage likely resulted in unrecognized iatrogenic disease as a result of the herb's intrinsic toxicity [92].

Extending this novel hypothesis, we have reviewed the use

Acknowledgment

The authors express their texts great appreciation to Professor Gerrit Jan Meulenbeld and Ms. Jie Wang, respectively, for their translations of ancient Sanscrit and Chinese texts. We thank Dr. Jovan Nikolic for his critique of the section on upper urinary tract cancer and Ms Annette Oestreicher for skilled editorial assistance. The National Institute of Environmental Health Sciences (grant ES-04068), Fogarty International Center (grant TW007042) and Croatian Ministry of Science supported the

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