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Semin Nephrol. 2019 May;39(3):284-296. doi: 10.1016/j.semnephrol.2019.02.007.

Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

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School of Medicine, University of Zagreb, Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Centre Zagreb, Zagreb, Croatia.
Department of Analytical, Environmental and Forensic Sciences, Medical Research Council-Public Health England Centre for Environment and Health, King's College London, London, United Kingdom; National Institute for Health Research Unit, Health Impact of Environmental Hazards, King's College London, in partnership with Public Health England and Imperial College London, London, United Kingdom.
Department of Biochemistry, Faculty of Science, Charles University, Prague 2, Czech Republic.
Serbian Medical Society, Branch Niš, Niš, Serbia.
Clinical Centre Serbia, Belgrade, Serbia.
Department of Human Biology and Toxicology, Faculty of Medicine and Pharmacy, University of Mons, Mons, Belgium.
Nephrology Department, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Nephrology Department, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium. Electronic address:


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.


Aristolochia species; Balkan endemic nephropathy; aristolochic acid; aristolochic acid nephropathy; upper tract urothelial carcinoma

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