Trends in the incidence of urothelial carcinoma in Taiwan after the ban on aristolochic acid-containing Chinese herbal preparations, 2001-2018: a national population-based cohort study.

PURPOSE: Urothelial carcinoma (UC) of the bladder (BUC) and the upper urinary tract (UTUC) are the two most common UCs. The incidence of UTUC in Taiwan is the highest worldwide. Aristolochic acid (AA) was identified as the main cause of UTUC in Taiwan. To explore trends in the incidence of UC in Taiwan after the ban on Chinese herbal preparations containing AA in 2003. METHODS: We used data from the Taiwanese National Health Insurance Research Database-linked Taiwanese National Cancer Registry for 2001-2018. UC was defined in accordance with the International Classification of Disease for Oncology. The age-standardized incidence was calculated on the basis of the World Health Organization standard population. Trends in the incidence were calculated as the annual percent change (APC) by using the Joinpoint regression program. RESULTS: Over the investigated period, the incidence of UC decreased at an average annual percent change (AAPC) of - 1.19% (95% CI - 1.47 ~ - 0.91, P < 0.001). However, the incidence in UTUC significantly increased, with the AAPC being 1.47% (95% CI 1.03 ~ 1.90, P < 0.001). In contrast, the incidence of BUC significantly decreased, with the overall AAPC being - 1.92% (95% CI - 2.3 ~ - 1.54, P < 0. 001). From 2001 to 2018, the overall incidence of UCs and BUC decreased in Taiwan, but the incidence of UTUC significantly increased. CONCLUSION: We suggest to apply the same review standards of new drug development process to herbal preparations and incorporate them into the adverse drug reaction or poison surveillance system. Most importantly, raise public awareness of the potential toxicity of phytotherapy.

Curcumin in the treatment of urological cancers: Therapeutic targets, challenges and prospects.

Urological cancers include bladder, prostate and renal cancers that can cause death in males and females. Patients with urological cancers are mainly diagnosed at an advanced disease stage when they also develop resistance to therapy or poor response. The use of natural products in the treatment of urological cancers has shown a significant increase. Curcumin has been widely used in cancer treatment due to its ability to trigger cell death and suppress metastasis. The beneficial effects of curcumin in the treatment of urological cancers is the focus of current review. Curcumin can induce apoptosis in the three types of urological cancers limiting their proliferative potential. Furthermore, curcumin can suppress invasion of urological cancers through EMT inhibition. Notably, curcumin decreases the expression of MMPs, therefore interfering with urological cancer metastasis. When used in combination with chemotherapy agents, curcumin displays synergistic effects in suppressing cancer progression. It can also be used as a chemosensitizer. Based on pre-clinical studies, curcumin administration is beneficial in the treatment of urological cancers and future clinical applications might be considered upon solving problems related to the poor bioavailability of the compound. To improve the bioavailability of curcumin and increase its therapeutic index in urological cancer suppression, nanostructures have been developed to favor targeted delivery.

Aristolochic acid and its effect on different cancers in uro-oncology.

PURPOSE OF REVIEW: To acquaint urologists with aristolochic acid nephropathy, an iatrogenic disease that poses a distinct threat to global public health. In China alone, 100 million people may currently be at risk. We illustrate the power of molecular epidemiology in establishing the cause of this disease. RECENT FINDINGS: Molecular epidemiologic approaches and novel mechanistic information established a causative linkage between exposure to aristolochic acid and urothelial carcinomas of the bladder and upper urinary tract. Noninvasive tests are available that detect urothelial cancers through the genetic analysis of urinary DNA. Combined with cytology, some of these tests can detect 95% of patients at risk of developing bladder and/or upper urothelial tract cancer. Robust biomarkers, including DNA-adduct and mutational signature analysis, unequivocally identify aristolochic acid-induced tumours. The high mutational load associated with aristolochic acid-induced tumours renders them candidates for immune-checkpoint therapy. SUMMARY: Guided by recent developments that facilitate early detection of urothelial cancers, the morbidity and mortality associated with aristolochic acid-induced bladder and upper tract urothelial carcinomas may be substantially reduced. The molecular epidemiology tools that define aristolochic acid-induced tumours may be applicable to other studies assessing potential environmental carcinogens.

Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma.

Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.

Reduction in the Incidence of Urological Cancers after the Ban on Chinese Herbal Products Containing Aristolochic Acid: An Interrupted Time-Series Analysis.

Cancer is a public health problem worldwide. Taiwan has a higher incidence rate of urological cancers than many Asian countries do. Aristolochic acid has been considered a potent carcinogen. In this study, we examined whether the cessation of the sales and preparation of aristolochic acid-containing Chinese herbal products (AA-CHPs) in Taiwan contributed to a decline in the incidence rates of bladder cancer, carcinomas of the renal pelvis and other urinary organs, and kidney cancer. We conducted an interrupted time-series analysis of long-term trends in the incidence rates of the aforementioned cancers between 1995 and 2013 in Taiwan. The incidence rates of bladder cancer and carcinomas of the renal pelvis and other urinary organs decreased considerably after 2008 and 2011, respectively. Notably, these change-of-slope time points occurred after the year 2003, when a ban on AA-CHPs was imposed in Taiwan. The ban on AA-CHPs in Taiwan was possibly associated with the reduction in the incidence of bladder cancer and carcinomas of the renal pelvis and other urinary organs.

Mutational signature of aristolochic acid: Clue to the recognition of a global disease.

Mutational signatures associated with specific forms of DNA damage have been identified in several forms of human cancer. Such signatures provide information regarding mechanisms of tumor induction which, in turn, can reduce exposure to carcinogens by shaping public health policy. Using a molecular epidemiologic approach that takes advantage of recent advances in genome sequencing while applying sensitive and specific analytical methods to characterize DNA damage, it has become increasingly possible to establish causative linkages between certain environmental mutagens and disease risk. In this perspective, we use aristolochic acid, a human carcinogen and nephrotoxin found in Aristolochia herbs, to illustrate the power and effectiveness of this multidisciplinary approach. The genome-wide mutational signature for this toxin, detected initially in cancers of the upper urinary tract, has subsequently been associated with cancers of the liver and kidney. These findings have significant implications for global public health, especially in China, where millions of individuals have used Aristolochia herbal remedies as part of traditional Chinese medicine and, thus, are at risk of developing aristolochic acid nephropathy and/or upper urinary tract carcinomas. The studies reported here set the stage for research into prevention and early detection, both of which will be required to manage a potentially devastating global disease.

[Aristolochic acid nephropathy ("Chinese herb nephropathy")]. / Néphropathie aux acides aristolochiques (« néphropathie aux herbes chinoises ¼).

Aristolochic acid nephropathy is a renal disease of toxic origin characterized by a progressive interstitial fibrosis and frequently associated with urinary tract cancer. It was initially reported in Belgium after the intake of slimming pills containing root extracts of a Chinese herb, Aristolochia fangchi. In the following decades, numerous cases have been reported worldwide, particularly in Asian countries. Several experimental models of aristolochic acid nephropathy (AAN) have been designed. They confirm the causal link between AA exposure and the onset of acute and chronic renal toxicity, as well as urinary tract cancer. These experimental models offer the opportunity to study the mechanisms of renal interstitial fibrosis and carcinogenesis. In terms of public health, the history of this nephropathy demonstrates that it is mandatory to submit all "natural medicinal products" to the same controls of efficacy, toxicity and conformity applied to the classical drugs derived from the pharmaceutical producers. Any unusual observation of renal failure and/or cancer of the urinary tract should lead to a questioning about any prior exposure to AA. The confirmation of the ingestion of AA containing compounds by phytochemical analysis is not always feasible. However, the renal biopsy remains a crucial diagnostic point through the demonstration of a hypocellular interstitial fibrosis with a decreasing corticomedullary gradient, mostly in advanced cases of kidney disease. Moreover, the detection of AA-related DNA adducts within a renal or urothelial tissue sample could confirm the prior AA exposure. The persistence of these specific DNA adducts in renal tissue is very long (up to 20 years). Finally, considering the highly carcinogenic properties of AA, a systematic endo-urological screening is absolutely necessary.

Differential microRNA expression in aristolochic acid-induced upper urothelial tract cancers ex vivo.

Aristolochic acid (AA) is a carcinogenic, mutagenic and nephrotoxic compound commonly isolated from members of the plant family of Aristolochiaceae (such as Aristolochia and Asarum) and used in Chinese herbal medicine. Use of AA and AA­containing plants causes chronic kidney disease (CKD) and upper urinary tract carcinoma (UUC); however, the underlying mechanism remains to be defined. miRNAs regulate a number of biological processes, including cell proliferation, differentiation and metabolism. This study explored differentially expressed miRNAs between AA­induced upper urothelial tract cancer (AAN­UUC) and non­AAN­UUC tissues. Patients with AAN­UUC and non­AAN­UUC (n=20/group) were recruited in the present study. Five tissue samples from each group were used for miRNA microarray profiling and the rest of the tissue samples were subjected to reverse transcription-quantitative polymerase chain reaction analysis including seven selected miRNAs for confirmation. A total of 29 miRNAs were differentially expressed between AAN­UUC and non­AAN­UUC tissues (P<0.05). TargenScan and Gene ontology analyses predicted the functions and targeted genes of these differentially expressed miRNAs, i.e. Akt3, FGFR3, PSEN1, VEGFa and AR. Subsequently, expression of the selected differentially expressed miRNAs (Hsa­miR­4795­5p, Hsa­miR­488, Hsa­miR­4784, Hsa­miR­330, Hsa­miR­3916, Hsa­miR­4274 and Hsa­miR­181c) was validated in another set of tissue samples. A total of 29 miRNAs were identified to be differentially expressed between AAN­UUC and non­AAN­UUC tissues and these miRNA target genes in FGFR3 and Akt pathways, which regulate cell growth and tumor progression, respectively.

Increased risk of urinary tract cancer in ESRD patients associated with usage of Chinese herbal products suspected of containing aristolochic acid.

INTRODUCTION: Both end-stage renal disease (ESRD) and urothelial cancer (UC) are associated with the consumption of Chinese herbal products containing aristolochic acid (AA) by the general population. The objective of this study was to determine the risk of UC associated with AA-related Chinese herbal products among ESRD patients. METHODS: We conducted a cohort study using the National Health Insurance reimbursement database to enroll all ESRD patients in Taiwan from 1998-2002. Cox regression models were constructed and hazard ratios and confidence intervals were estimated after controlling for potential confounders, including age, sex, residence in region with endemic black foot disease, urinary tract infection, and use of non-steroidal anti-inflammatory drugs and acetaminophen. RESULTS: A total of 38,995 ESRD patients were included in the final analysis, and 320 patients developed UC after ESRD. Having been prescribed Mu Tong that was adulterated with Guan Mu Tong (Aristolochia manshuriensis) before 2004, or an estimated consumption of more than 1-100 mg of aristolochic acid, were both associated with an increased risk of UC in the multivariable analyses. Analgesic consumption of more than 150 pills was also associated with an increased risk of UC, although there was little correlation between the two risk factors. CONCLUSION: Consumption of aristolochic acid-related Chinese herbal products was associated with an increased risk of developing UC in ESRD patients. Regular follow-up screening for UC in ESRD patients who have consumed Chinese herbal products is thus necessary.

The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review.

It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors' experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.

Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.

Aristolochic acid (AA), a component of all Aristolochia-based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA-induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam-DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T-to-T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam-DNA adducts and A:T-to-T:A transversions in TP53 were defined as AA-UUC, whereas patients lacking both of these biomarkers were classified as non-AA-UUC. Cases with either biomarker were classified as possible-AA-UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA-UUC, possible-AA-UUC and non-AA-UUC, respectively. AA-UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end-stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible-AA-UUC and non-AA-UUC patients. All 14 patients who developed contralateral UUC had aristolactam-DNA adducts; ten of these also had signature mutations. The contralateral UUC-free survival period was shorter in AA-UUC compared to possible- or non-AA-UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA-UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

Nutritional chemoprevention of urinary tract tumors (UTT) induced by lithogenic agents: risk for UTT in children exposed to melamine-contaminated milk formulas.

Urinary tract tumors are tenth in frequency, and many environmental carcinogens are excreted by urine. Interplay between chronic inflammatory urolithiasis and urothelial carcinogenesis is not well understood. Experimental evidences show that dietary melamine induce these events even at low concentrations. This is important because thousands of children were exposed to melamine through intentionally contaminated milk formula worldwide. We propose that an increased risk for urinary tumors in adult life may occur and screenings for early urinary signs may be necessary. Therefore, urothelial biology, melamine carcinogenic potential, and related epidemiology are discussed, recommending a preventive dietary polyunsaturated fatty acid-based supplementation, since they modulate such interplay in rodents.

Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy.

Chinese herbs nephropathy (CHN) and Balkan endemic nephropathy (BEN) are chronic tubulointerstitial renal diseases associated with urothelial carcinoma. The clinical expression and pathological lesions observed at different stages of CHN and BEN are strikingly similar. Both have been linked to exposure to aristolochic acid (AA), a powerful nephrotoxin and human carcinogen. Jelakovic et al. present molecular epidemiological evidence relating urothelial carcinoma in patients with BEN to dietary exposure to AA. It is time to abandon the terms 'CHN' and 'BEN' and introduce 'aristolochic acid nephropathy' to cover both clinical conditions.

Various dietary polyunsaturated fatty acids modulate acrylamide-induced preneoplatic urothelial proliferation and apoptosis in mice.

To investigate whether various dietary fats affected preneoplatic lesions of urinary tract in acrylamide (ACR)-treated mice. Eighty Kunming mice were initiated with ACR at dose 10mg/kg bw, and fed with different polyunsaturated fatty acid (PUFA): 6% fish oil (enriched in n-3 PUFA), 6% corn oil (enriched in n-6), 6% olein (enriched in n-9, an EFA deficiency inducer), 10% fish oil, 10% corn oil, 10% olein and a commercial chow. Animals were autopsied 22 weeks. The liver fatty acid profile showed a close correlation with dietary sources, exhibiting macroscopic and biochemical EFA-deficient (EFAD) characteristics in ACR mice with olein. The frequency of simple urothelial hyperplasia (H) and dysplasia/carcinoma in situ (D/CIS) was significantly higher in ACR mice with corn oil or olein compared to ACR mice with commercial chow. Proliferation and abnormal luminal localized mitosis, also expression of proliferating cell nuclear antigen (PCNA), significantly increased in ACR mice with corn oil and olein than in ACR mice with commercial chow; moreover, abnormal apoptotic/mitosis ratio, expression of caspase-3, decreased in ACR mice with both olein and corn oil. Fish oil took no significant effect on almost all the parameters in ACR mice in this study. Results suggest that dietary PUFA modulate preneoplastic proliferation in ACR mice; n-6 PUFA (corn oil) and EFAD status (n-9 PUFA) exhibits a promoting activity; whereas, fish oil, rich in n-3 fatty acids, exhibits somewhat attenuated effect, and needs further research.

Population-based case-control study of Chinese herbal products containing aristolochic acid and urinary tract cancer risk.

BACKGROUND: Consumption of Chinese herbs that contain aristolochic acid (eg, Mu Tong) has been associated with an increased risk of urinary tract cancer. METHODS: We conducted a population-based case-control study in Taiwan to examine the association between prescribed Chinese herbal products that contain aristolochic acid and urinary tract cancer. All patients newly diagnosed with urinary tract cancer (case subjects) from January 1, 2001, to December 31, 2002, and a random sample of the entire insured population from January 1, 1997, to December 31, 2002 (control subjects), were selected from the National Health Insurance reimbursement database. Subjects who were ever prescribed more than 500 pills of nonsteroidal anti-inflammatory drugs and/or acetaminophen were excluded, leaving 4594 case patients and 174,701 control subjects in the final analysis. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by using multivariable logistic regression models for the association between prescribed Chinese herbs containing aristolochic acid and the occurrence of urinary tract cancer. Models were adjusted for age, sex, residence in a township where black foot disease was endemic (an indicator of chronic arsenic exposure from drinking water [a risk factor for urinary tract cancer]), and history of chronic urinary tract infection. Statistical tests were two-sided. RESULTS: Having been prescribed more than 60 g of Mu Tong and an estimated consumption of more than 150 mg of aristolochic acid were independently associated with an increased risk for urinary tract cancer in multivariable analyses (Mu Tong: at 61-100 g, OR = 1.6, 95% CI = 1.3 to 2.1, and at >200 g, OR = 2.1, 95% CI = 1.3 to 3.4; aristolochic acid: at 151-250 mg, OR = 1.4, 95% CI = 1.1 to 1.8, and at >500 mg, OR = 2.0, 95% CI = 1.4 to 2.9). A statistically significant linear dose-response relationship was observed between the prescribed dose of Mu Tong or the estimated cumulative dose of aristolochic acid and the risk of urinary tract cancer (P < .001 for both). CONCLUSIONS: Consumption of aristolochic acid-containing Chinese herbal products is associated with an increased risk of cancer of the urinary tract in a dose-dependent manner that is independent of arsenic exposure.

De novo urothelial carcinoma in kidney transplant patients with end-stage aristolochic acid nephropathy in China.

OBJECTIVE: Aristolochic acid nephropathy (AAN) is a progressive renal interstitial fibrosis disease that was initially reported among a Belgian cohort of about 50 patients after the intake of diet pills containing the Chinese herb Aristolochia fangchi. In addition to renal disease, foci of AAN show increased incidences of urothelial carcinomas (UC). Immunosuppression is associated with an increased risk for the development of different malignancies. Our aim was to examine the outcomes of UC among patients with AAN after transplantation in China, the cradle of this traditional medicine. PATIENTS AND METHODS: We performed a retrospective evaluation of the charts and pathology reports of 1612 renal transplant recipients treated at our 2 institutions. RESULTS: From January 1998 to December 2006, we performed cadaveric kidney transplantations in 17 patients with AAN, all of whom were treated with cyclosporine plus azathioprine or mycophenolate mofetil plus prednisone. One-year graft survival was 100%. During the mean follow-up of 57 months (range, 21-108 months), 9 recipients (52.9%) developed UC, compared with a 0.46% prevalence of urinary tract tumors among other Chinese kidney transplant recipients. The age at which the diagnosis was made ranged from 39 to 66 years (mean, 53.6 +/- 6.8 years). Among the 9 patients with UC, 8 cases (88.9%) involved the upper urinary tract: bilateral, 3 cases, 37.5%; unilateral, 5 cases, 62.5%. In 1 patient only a bladder tumor was detected. Two patients showed the bladder, synchronous bilateral ureter, and pelvis to be involved. All patients with UC underwent surgical treatment, recovering uneventfully with functioning grafts after tumor excision, except 1 patient who underwent nephrectomy of the transplanted kidney. Six patients (75%) experienced recurrences during the follow-up period. Three patients died within a mean of 20 months (range, 1-42 months) after tumor excision. CONCLUSIONS: The risk for UC is increased among patients with AAN after transplantation. Regular screening for early detection of malignancy is mandatory. Longer follow-up and results from other transplant centers are needed to further investigate the relationship between AAN and UC among renal transplant patients.

New molecular and field evidences for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor.

To find out whether ochratoxin A (OTA), citrinin (CIT), aristolochic acids (AA) are etiologic agents of Balkan endemic nephropathy (BEN) or Chinese herbal nephrotoxicity, and associated urinary tract tumor (UTT), we have compared (i) in human kidney cell culture, the DNA adduct formation and persistence of OTA/CIT and AA adducts (ii) analyzed DNA adduct in several tumors from human kidney suspected to be exposed to either OTA and CIT, or AAs (iii) analyzed OTA, CIT, and AA in food. In kidney cell cultures, formation of specific OTA-DNA adduct and AA-DNA adduct were detected in the same range (around 10 adducts/10(9) nucleotides) and were time- and dose-dependent. After 2 days all disappeared. DNA adduct related to OTA and CIT are found in human kidney tissues from Balkans, France, and Belgium whereas no DNA adducts related to AA could be found in any tumors of BEN patients from Croatia, Bulgaria, or Serbia. No DNA adduct was found in kidney biopsy or necropsy of the French women suspected to be exposed to AA. OTA and CIT are more frequently found in rural area. AA was never detected. All these plead for implication of mycotoxins, especially OTA, in BEN and UTT.

Renal interstitial fibrosis and urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi).

A new renal disease called 'Chinese-herb nephropathy' (CHN) has been reported to occur in women who have ingested slimming pills containing powdered extracts of the Chinese herb Stephania tetrandra (ST). Moderate to end-stage renal disease developed, requiring renal replacement therapy by dialysis or transplantation. Phytochemical analyses of the pills revealed the presence of aristolochic acids (AA) instead of tetrandrine, suggesting the substitution of ST (Han fang ji) by Aristolochia fangchi containing nephrotoxic and carcinogenic AA. A typical histological feature of CHN is a progressive interstitial fibrosis leading to a severe atrophy of the proximal tubules, as documented by the urinary excretion rates of markers of tubular integrity (reduction of neutral endopeptidase enzymuria and high levels of microproteinurias). Removal of the native kidneys and ureters in end-stage CHN patients provided a high prevalence of urothelial carcinoma (46%). Tissue samples contained AA-related DNA adducts, which are not only specific markers of prior exposure to AA but are also directly involved in tumorigenesis. Exposure to Aristolochia species (spp.) is associated with the development of renal interstitial fibrosis (CHN) and urothelial cancer in humans. Health professionals should be aware that in traditional Chinese medicine, Aristolochia spp. are considered interchangeable with certain other herbal ingredients and are also sometimes mistaken for ST, Akebia, Asarum, Clematis spp. and Cocculus spp. in herbal remedies.