Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

[Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility]. / Tumeurs des voies excrétrices urinaires supérieures sporadiques: identification de l'interaction entre l'exposition aux carcinogènes environnementaux et la susceptibilité génétique des individus.

Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence.

Urothelial malignant disease and Chinese herbal nephropathy.

We have previously reported occurrence of a specific type of nephropathy due to ingestion of Chinese herbs (Chinese herbal nephropathy [CHN]) in two patients in the UK. These cases highlighted the role of aristolochic acid in causing this nephropathy, which was first described in a Belgian cohort. We now report development of invasive transitional cell carcinoma of the urinary tract associated with the presence of aristolochic acid-DNA adducts in one of these patients. This work clearly shows the carcinogenic potential of aristolochic acid in this new type of nephropathy.

Urothelial lesions in Chinese-herb nephropathy.

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.

Analgesics, cigarette smoking, and other risk factors for cancer of the renal pelvis and ureter.

Results from a population-based case-control study of cancer of the renal pelvis and ureter are reported. Telephone interviews were conducted with 187 residents of Los Angeles County diagnosed with cancer of the renal pelvis and ureter over a 4-year period ending December 31, 1982, and with individually sex-, age- and race-matched neighborhood controls. The major risk factor identified for cancer of the renal pelvis and ureter was cigarette smoking. Subjects who smoked more than 25 years had a relative risk of 4.5 of developing these tumors, compared to nonsmokers (P less than 0.0001). Heavy use of over-the-counter analgesics was also associated with a significant increase in risk; it appears that an elevated risk was conveyed by all the major active constituents of those compounds currently marketed in the United States, aspirin, caffeine, and acetaminophen. Persons who had used these drugs for 30 consecutive days at any time in their life preceding diagnosis had twice the risk of developing cancer of the renal pelvis or ureter compared to persons not reporting such use (P less than 0.01). Heavy coffee drinkers (greater than or equal to 7 cups/day) had a 1.8-fold increase in risk compared to nondrinkers. Although risk tended to increase with increasing consumption, this result was not statistically significant. The risk associated with heavy coffee consumption was reduced to 1.3 after adjusting for smoking. Nine cases compared to no controls reported a first degree relative with kidney cancer. A history of kidney stones was associated with an increased risk of cancer of the ureter (relative risk = 2.5) that was not, however, statistically significant.