phenanthrenes and Kidney-Failure--Chronic

Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.

Topics: Animals; Aristolochic Acids; Body Weight; Carcinoma, Transitional Cell; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Fibrosis; Injections, Subcutaneous; Kidney; Kidney Failure, Chronic; Kidney Tubules; Male; Pelvic Neoplasms; Phenanthrenes; Rats; Rats, Wistar; Reference Values; Sarcoma; Sodium Chloride; Survival Analysis

Topics: Aristolochic Acids; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Obesity; Phenanthrenes; Phytotherapy; Risk

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.

Topics: Aristolochic Acids; Carcinogens; Carcinoma, Transitional Cell; Drugs, Chinese Herbal; Female; Humans; Kidney Failure, Chronic; Middle Aged; Phenanthrenes; Ureteral Neoplasms

Topics: Aristolochic Acids; Drugs, Chinese Herbal; Eczema; Female; Humans; Kidney Failure, Chronic; Middle Aged; Phenanthrenes

Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic.. The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated.. Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma.. The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Topics: Anti-Obesity Agents; Aristolochic Acids; Carcinogens; DNA Adducts; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Ochratoxins; Phenanthrenes; Prevalence; Risk Factors; Ureter; Urologic Neoplasms; Urothelium

Topics: Aristolochic Acids; Carcinogens; Dietary Supplements; Drugs, Chinese Herbal; Female; Humans; Kidney Failure, Chronic; Legislation, Drug; Phenanthrenes; United States; United States Food and Drug Administration; Urologic Neoplasms; Urothelium

Topics: Anti-Obesity Agents; Aristolochic Acids; Drugs, Chinese Herbal; Humans; Kidney Failure, Chronic; Phenanthrenes; Urologic Neoplasms; Urothelium

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.

Topics: Aristolochic Acids; Biopsy; Drugs, Chinese Herbal; Eczema; Female; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Middle Aged; Phenanthrenes

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.

Topics: Adult; Aristolochic Acids; Belgium; Drugs, Chinese Herbal; Female; France; Humans; Kidney Failure, Chronic; Middle Aged; Phenanthrenes