Balkan endemic nephropathy (BEN) is a disease found in Romania and neighboring countries in the Balkan area. In Romania, BEN is most prevalent in Mehedinti County, located in the South of Romania near the Danube River. The etiology of the disease is as yet unknown. One of the current hypotheses concerning BEN etiology is an involvement of aristolochic acid (AA). BEN bears many similarities to aristolochic nephropathy, which is developed due to the use of Chinese herbs as therapeutic remedies in slimming diets. This paper analyzes the involvement of therapeutic remedies based on AA in the BEN found in Mehedinti County, where these herbs have been traditionally used. The presence of AA in the plasma of BEN patients as well as of other subjects, including healthy relatives of these patients and other persons from the BEN-affected area, has been analyzed. No AA was detected in the plasma of the studied subjects. This proves the absence, at the current time, of an AA contribution in the analyzed subjects. Therapeutic remedies based on AA have been used in the BEN-affected area. We were not able to reveal direct relationships between these remedies and either the development of BEN in dialyzed patients or the development of urinary-tract tumors in dialyzed patients with urothelial tumors. Therapeutic remedies based on Aristolochiaclematitis may play a stimulating role in BEN with regard to its development and the development of urinary-tract tumors. There may be a relationship between BEN and cumulative previous exposure to low doses of AA due to the consumption of contaminated foodstuffs, which could add to any contributions by therapeutic remedies.

Trască E, Buzulica R, Trasca ET: Pelvisul renal. Craiova, Ed. Medicală Universitară, 2005.
Stefanovic V, Toncheva D, Atanasova S, Polenakovic M: Etiology of Balkan endemic nephropathy and associated urothelial cancer. Am J Nephrol 2006;26:1–11.
Ivic M: The problem of etiology of endemic nephropathy. Acta Fac Med Naiss 1970;1:29–37.
Dimic A: Horse poisoning by ‘wolf’s foot’ (Aristolochiaclematitis L.)(horse poisoning by ‘birthworth’). Belgrade, Serbia. Vojnotechnicki glasnik 1954, pp 3–35.
Martincevic M: Toxic action of Aristolochiaclematitis on the kidneys of horses. Veterinarski Archiv 1957;27:51–59.
Grollman AP, Shibutani S, Moriya M, Miller F, Wu L, Moll U, Fernandez A, Rosenquist T, Medverec Z, Jakovina K, Brdar B, Slade N, Tureski RJ, Goodenouch A, Rieger R, Vukevic M, Jelakovic B: Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci USA 2007;104:12129–12134.
Vanherweghem JL, Depierreux M, Tielmans C, Abramovicz D, Dratwa M, Jadoul M, Vandervelde D, Vanhaelen-Fastre R, Vanhaelen M: Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993;341:892–893.
Nortier JL, Depierreux MF, Vanhaelen M, Muniz Martinez MC, Arlt VM, Schmeiser HH, Debelle F, Lemy A, Deschodt-Lanckman HM, Vanherweghem JL: Aristolochic acid nephropathy in Belgium. A clinical and epidemiologic update. Coll Antropol 2006;30(suppl 1):30.
Batuman V: Fifty years of Balkan endemic nephropathy: daunting questions, elusive answers. Kidney Int 2006;69:723–729.
Arlt WM, Stiborova M, Schmeiser HN: Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 2002;17:265–277.
Shibutani S, Suzuki N, Fernandez A, Leko N, Jelakovic B, Grollman AP: Balkan endemic nephropathy: a preventable environmental disease. Cancer Epidemiol Biomarkers Prev 2005;14:2717S.
Debelle FD, Nortier JL, De Prez EG, Grabar CH, Vienne AR, Salmon IJ, Deschodt-Lanckman MM, Vanherweghem JL: Aristolochic acids induce chronic renal failure with interstitial fibrosis in salt-depleted rats. J Am Soc Nephrol 2002;13:431–436.
Hranjec T, Kovac A, Kos J, Mao W, Chen JJ, Grollman AP, Jelakovic B: Endemic nephropathy: the case for chronic poisoning by aristolochia. Croat Med J 2005;46:116–125.
Shibutani S, Dong H, Suzuki N, Ueda S, Miller F, Grollman AP: Selective toxicity of aristolochic acids I and II. Drug Metab Dispos 2007;35:1217-1222.
Nortier JL, Muniz MC, Schmeiser HH, Arlt VM, Bieler CA, Petein M, Depierreux MF de Pauw L, Abramovicz D, Vereerstraeten D, Vanherweghem JL: Urothelial carcinoma associated with the use of a Chinese herb (Aristolochiafangchi) N Engl J Med 2000;342:1686–1692.
Jelakovic B: Endemic (Balkan) nephropathy and aristolochic acid. Lessons from Croatia. Coll Antropol 2006;30(suppl 1):31.
Vineis P, Perera F: DNA adduct as markers of exposure to carcinogens and risk of cancer. Int J Cancer 2000;88:325–328.
Arlt VM, Lord GM, Nortier JL, Simoes ML, Phillips DH, Hollstein M, Schmeiser HH: Aristolochic acid mutagenesis: a molecular clue to the etiology of Balkan endemic nephropathy-associated urothelial cancer? Coll Antropol 2006;30(suppl 1):27.
Arlt VM, Stiborova M, von Brocke J, Simoes ML, Lord GM, Nortier JL, Hollstein M, Phillips DH, Schmeiser HH: Aristolochic acid mutagenesis: molecular clues to the etiology of Balkan endemic nephropathy-associated urothelial cancer. Carcinogenesis 2007;28:2253–2261.
Shibutani S, Dong H, Gao S, Fernandes A, Miller F, Rosenquist TA: Mouse model of aristolochic acid nephropathy. Coll Antropol 2006;30(suppl 1):27.
Wang G, Wang ZM, Sun QS: Advance in studies on pharmacokinetics of aristolochic acid I. Zhongguo Zhong Yao Za Zhi 2006;31:1573–1575.
De Jonge H, Vanrenterghem Y: Aristolochic acid: the common culprit of Chinese herbs nephropathy and Balkan endemic nephropathy. Nephrol Dial Transplant 2008;23:39–41.
Cosyns JP, Jadoul M, Squifflet IP, De Plaen JF, Ferluga D, van Ypersele de Strihou C: Chinese herb nephropathy: a clue to Balkan endemic nephropathy. Kidney Int 1994;45:1680–1688.
Schmeiser HH, Stiborová M, Arlt VM: Chemical and molecular basis of the carcinogenicity of Aristolochia plants. Curr Opin Drug Discov Devel 2009;12:141–148.
Fistrek M, Kovac-Peic A, Kos J, Pecin I, Barasic M, Hadzibegovic I, Danic A, Misic M, Pavlovic I, Dika Z, Miletic-Medved M, Cvitkovic A, Bistrovic D, Grollmann AP, Jelakovic B: Ingestion of herbal tea in Croatian endemic area. Acta Medica Croatica 2008;62 (suppl 1):110.
Arlt VM, Stiborová M, vom Brocke J, Simões ML, Lord GM, Nortier JL, Hollstein M, Phillips DH, Schmeiser HH: Aristolochic acid mutagenesis: molecular clues to the aetiology of Balkan endemic nephropathy-associated urothelial cancer. Carcinogenesis 2007;28:2253–2261.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.