Balkan endemic nephropathy: an update on its aetiology

Abstract

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3-7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.

Keywords: Aristolochic acid; Aristolochic acid nephropathy; Balkan endemic nephropathy; Disease aetiology; Environmental and genetic factors; Upper urothelial cancer.

Fig. 1

Distribution of BEN foci in Bosnia-Herzegovina, Croatia, Serbia, Bulgaria, and Romania (https://en.wikipedia.org/wiki/Danubian_endemic_familial_nephropathy#/media/File:Balkan_endemic_nephropathy_map.svg)

Fig. 2

Aristolochia clematitis (a) and the formula of the major components of the AA plant product, aristolochic acid I (AAI) and aristolochic acid II (AAII) (b)

Fig. 3

Metabolic activation and DNA adduct formation of aristolochic acid I (AAI) and II (AAII); 7-(deoxyadenosin-N ⁶-yl)aristolactam I or II (dA-AAI or dA-AAII), 7-(deoxyguanosin-N ²-yl)aristolactam I or II (dG-AAI or dG-AAII). Inserts Autoradiographic profiles of DNA adducts detected by ³²P-postlabelling showing the analysis of renal tissue of an CHN/AAN patient in Belgium (Nortier et al. 2000) and a patient with end-stage renal disease (ESRD) and UCC living in an area endemic for BEN (Arlt et al. 2002b)

Fig. 4

Mutation pattern in TP53 of UUC. Mutation data from human tumours were obtained from the IARC TP53 mutation database (http://www.p53.iarc.fr; R18 version). a TP53 mutation pattern in AAN-associated urothelial cancer in the United Kingdom (n = 1) (Lord et al. 2004). b TP53 mutation pattern in BEN-associated urothelial cancer in Croatia, Bosnia, Serbia (n = 59) (Grollman et al. ; Moriya et al. 2011). c TP53 mutation pattern in AAN-associated urothelial cancer in Taiwan (n = 113) (Chen et al. 2012). d TP53 mutation pattern in urothelial cancer not associated with AA exposure (n = 1127). Organs included: kidney, bladder, renal pelvis, ureter and other urinary organs. Morphology inclusion criteria: carcinoma not otherwise specified, carcinoma in situ not otherwise specified, dysplasia not otherwise specified, papillary carcinoma not otherwise specified, transitional cell carcinoma in situ, transitional carcinoma not otherwise specified and urothelial papilloma not otherwise specified

Fig. 5

Activation and detoxication pathways of AAI. dA-AAI 7-(deoxyadenosin-N ⁶-yl)aristolactam I, dG-AAI 7-(deoxyguanosin-N ²-yl)aristolactam I, CYP1A1/2 cytochrome P450 1A1 and 1A2, CYP2C cytochrome P450 2C, NQO1 NAD(P)H:quinone oxidoreductase, UGT UDP glucuronosyltransferase, SULT sulfotransferase

Fig. 6

Contributions of CYP enzymes to AAIa formation in human (a) and rat livers (b)