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      Update of aristolochic acid nephropathy in Korea

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          Abstract

          Background/Aims

          The true incidence of aristolochic acid nephropathy (AAN) is thought to be underestimated because numerous ingredients known or suspected to contain aristolochic acid (AA) are used in traditional medicine in Korea.

          Methods

          We collected data on cases of AAN since 1996 via a database in Korea. We evaluated the year of AAN development, route to obtaining AA-containing herbal medicine, gender, reason for taking AA-containing herbal medicine, clinical manifestations, histological findings, phytochemical analysis, and prognosis of patients with AAN.

          Results

          Data on 16 cases of AAN were collected. Thirteen cases developed AAN before and three cases after the prohibition of AA-containing herbal medicine by the Korea Food and Drug Administration. Patients were prescribed AA-containing herbal medicine from oriental clinics or had purchased it from traditional markets. AAN was distributed in all age groups. Young females were most commonly exposed to AA-containing herbal medicine for slimming purposes and postpartum health promotion, while older adults took AA-containing compounds for the treatment of chronic diseases. The most common symptoms presented at hospitalization were nausea and vomiting, and acute kidney injury was accompanied by Fanconi syndrome in almost half of the patients. Phytochemical analysis of AA in herbal medicine was available in six cases. Progression to end stage renal disease (ESRD) was observed in seven patients (43.8%), and five patients (31.3%) had progressed to ESRD within 6 months of diagnosis.

          Conclusions

          Our report shows that patients were still exposed to AA-containing herbal medicine and that there is a possibility of underdiagnosis of AAN in Korea. A stronger national supervision system of herbal ingredients and remedies in oriental medicine is needed to prevent AAN.

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          Most cited references28

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          Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

          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.
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            Aristolochic acid nephropathy: a worldwide problem.

            Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain aristolochic acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.
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              Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs.

              Two similar cases of rapidly progressive fibrosing interstitial nephritis in young women who followed the same slimming regimen prompted us to conduct an epidemiological survey of the nephrology centres of Brussels and to further investigate the exact nature of this slimming treatment. Seven other women under the age of 50 in terminal or preterminal renal failure were admitted for dialysis in 1991 and 1992. They had all followed a slimming regimen in the same medical clinic. Renal biopsy samples in eight of the nine cases showed extensive interstitial fibrosis without glomerular lesions. Two of the patients were seen for the first time in terminal renal failure and were started immediately on dialysis. For the seven other women, the nephropathy was characterised by a rapid deterioration in renal function, with initial serum creatinine doubling within about 3 months. The clinic had specialised in slimming treatments for the previous 15 years without any problems. In May, 1990, therapy was changed, with the introduction of two Chinese herbs (Stephania tetrandra and Magnolia officinalis). In June, 1992, three of twenty-five randomly selected women who had followed the same regimen during at least 3 months from 1990 had impaired renal function. Chemical analysis of some brands of these Chinese herbs did not show nephrotoxic contaminants of fungal or plant origin (ochratoxin or aristolochic acid) or adulteration by diuretics or antiinflammatory drugs. However, the medicinal preparation of the capsules taken by patients had different alkaloid profiles from those expected in Chinese plants. The striking relation between a specific type of fibrosing interstitial nephritis in young women and a slimming treatment involving Chinese herbs adds support to the arguments against uncontrolled therapy with herbal preparations.
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                Author and article information

                Journal
                Korean J Intern Med
                Korean J. Intern. Med
                KJIM
                The Korean Journal of Internal Medicine
                The Korean Association of Internal Medicine
                1226-3303
                2005-6648
                September 2018
                20 March 2018
                : 33
                : 5
                : 961-969
                Affiliations
                [1 ]Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
                [2 ]Department of Internal Medicine, The Research Institute for Transplantation, and Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Korea
                [3 ]Division of Nephrology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea
                [4 ]Nephrology Clinic, National Cancer Center Hospital, Goyang, Korea
                [5 ]Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
                Author notes
                Correspondence to Chul Woo Yang, M.D. Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Korea Tel: +82-2-2258-6037 Fax: +82-2-536-0323 E-mail: yangch@ 123456catholic.ac.kr
                Article
                kjim-2016-288
                10.3904/kjim.2016.288
                6129635
                29551056
                28c20384-cea9-4e5f-8bbb-fd0396de7be2
                Copyright © 2018 The Korean Association of Internal Medicine

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 26 September 2016
                : 31 October 2016
                : 8 November 2016
                Categories
                Original Article
                Nephrology

                Internal medicine
                chinese herbal medicine,aristolochic acid,renal toxicity
                Internal medicine
                chinese herbal medicine, aristolochic acid, renal toxicity

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