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Balkan Endemic Nephropathy: an Update on Its Aetiology

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Balkan Endemic Nephropathy: an Update on Its Aetiology Arch Toxicol DOI 10.1007/s00204-016-1819-3 REVIEW ARTICLE Balkan endemic nephropathy: an update on its aetiology Marie Stiborová1 · Volker M. Arlt2,3 · Heinz H. Schmeiser4 Received: 17 June 2016 / Accepted: 4 August 2016 © The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Balkan endemic nephropathy (BEN) is a In fact dietary ingestion of AA along with individual unique, chronic renal disease frequently associated with genetic susceptibility provides a scenario that plausibly upper urothelial cancer (UUC). It only affects residents can explain all the peculiarities of BEN such as geograph- of specific farming villages located along tributaries of ical distribution and high risk of urothelial cancer. For the the Danube River in Bosnia-Herzegovina, Croatia, Mac- countries harbouring BEN implementing public health edonia, Serbia, Bulgaria, and Romania where it is esti- measures to avoid AA exposure is of the utmost impor- mated that ~100,000 individuals are at risk of BEN, while tance because this seems to be the best way to eradicate ~25,000 have the disease. This review summarises current this once mysterious disease to which the residents of findings on the aetiology of BEN. Over the last 50 years, BEN villages have been completely and utterly at mercy several hypotheses on the cause of BEN have been formu- for so long. lated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecu- Keywords Balkan endemic nephropathy · Disease lar epidemiological studies provide a strong case that aetiology · Upper urothelial cancer · Environmental chronic dietary exposure to aristolochic acid (AA) a prin- and genetic factors · Aristolochic acid nephropathy · cipal component of Aristolochia clematitis which grows Aristolochic acid as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still Abbreviations enigmatic features of BEN that need to be resolved is why AA Aristolochic acids the prevalence of BEN is only 3–7 %. This suggests that AAI Aristolochic acid I individual genetic susceptibilities to AA exist in humans. AAIa Aristolochic acid Ia (8-hydroxyaristolochic acid I) AAII Aristolochic acid II * Marie Stiborová AAN Aristolochic acid nephropathy [email protected] AhR Aryl hydrocarbon receptor 1 Department of Biochemistry, Faculty of Science, Charles ARE Antioxidant response element University, Albertov 2030, 128 40 Prague 2, Czech Republic BEN Balkan endemic nephropathy 2 Analytical and Environmental Sciences Division, MRC‑PHE CHN Chinese herbs nephropathy Centre for Environmental and Health, King’s College CKD Chronic kidney disease London, 150 Stamford Street, London SE1 9NH, UK CYP Cytochrome P450 3 NIHR Health Protection Research Unit in Health Impact dA-AAI 7-(Deoxyadenosin-N6-yl)aristolactam I of Environmental Hazards at King’s College London dA-AAII 7-(Deoxyadenosin-N6-yl)aristolactam II in partnership with Public Health England, Franklin–Wilkins 2 Building, 150 Stamford Street, London SE1 9NH, UK dG-AAI 7-(Deoxyguanosin-N -yl)aristolactam I dG-AAII 7-(Deoxyguanosin-N2-yl)aristolactam II 4 Division of Radiopharmaceutical Chemistry (E030), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, dG-OTA OTA-deoxyguanosine adduct 69120 Heidelberg, Germany EFSA European Food Safety Authority 1 3 Arch Toxicol ESRD End-stage renal disease (Danilovic et al. 1957; Tanchev et al. 1956). The disease HRN NADPH:cytochrome P450 reductase null affects residents of rural farming villages located along HSPG2 Heparan sulphate proteoglycan 2 the tributaries of the Danube River in Bosnia-Herzego- HUFs Hupki mouse embryo fibroblasts vina, Croatia, Macedonia, Serbia, Bulgaria, and Romania IARC International Agency for Research on Cancer (Fig. 1) (Grollman 2013; Pavlovic 2013; Pfohl-Leszkowicz NAT N,O-Acetyltransferase 2009; Radovanović 2002; Stefanovic 1983). NQO1 NAD(P)H:quinone oxidoreductase A characteristic feature of BEN is its close association OTA Ochratoxin A with upper urothelial cancer (UUC) of the renal pelvis and ROS Reactive oxygen species ureter (Miletić-Medved et al. 2005; Radovanovic 2002; SULT Sulfotransferase Stefanovic 1983; Stefanovic and Radovanovic 2008). UGT UDP glucuronosyltransferase These UUCs are mostly carcinomas (Toncheva et al. UUC Upper urothelial cancer 2014) and are the most common causes of death in BEN XRE Xenobiotic response element patients. BEN patients also have a higher risk of develop- ing UUC after kidney transplantation (Basic-Jukic et al. 2007). The difference in the prevalence of UUC between Introduction the general kidney transplant population (0.69 %) and the BEN population (43.7 %) is enormous, confirming the Balkan endemic nephropathy (BEN) is a chronic tubu- association of BEN with UUC. In BEN patients, bilateral lointerstitial nephropathy characterised by an insidious nephroureterectomy before transplantation has been sug- onset and gradual progression to end-stage renal disease gested as a preventive measure (reviewed in Stefanovic (ESRD) which was first described more than 60 years ago et al. 2015). 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) 1 3 Arch Toxicol Epidemiology, pathology, clinical features permanent. Loss of urine concentration capacity precedes and diagnosis of BEN a decrease in the glomerular filtration rate (Alecković et al. 2010; Arsenović et al. 2005; Dimitrov et al. 2006). The most remarkable feature of BEN is its endemic Kidney atrophy has been suggested as one of the criteria nature and its familial but not inherited pattern of distri- for the clinical diagnosis of BEN. However, investigations bution. Nevertheless, besides the endemic regions shown of kidney status have shown a variable decrease in kidney in Fig. 1, sporadic cases of BEN were also found in other size with very small contracted kidneys in ESRD (Radonić regions (Stefanovic et al. 2009, 2015). BEN only affects and Radosević 1992). Unfortunately, there are no diagnos- the rural farming population, but has never been found tic markers of BEN, which are characteristic for the dis- among inhabitants of larger cities. The disease exhibits a ease. However, the set of epidemiological, clinical and bio- focal occurrence within certain villages where remarkably chemical data along with the pattern of pathologic injury, in affected villages are often in close proximity to unaffected the absence of any other renal disease, is highly suggestive villages (Bamias and Boletis 2008). Moreover, within the of BEN in affected countries. The diagnostic criteria for same village, affected and spared households often live in BEN were described for the first time more than 50 years close proximity. In a single household, numerous members ago and have been improved continuously since then. How- of one or several generations can be affected (Stefanovic ever, criteria differed in affected countries and a meeting et al. 2015); therefore, it has been postulated that only per- was held in Zagreb, Croatia, in 2006 (Grollman and Jela- sons “living under the same roof and eating the same food” kovic 2007) to establish more unified diagnostic criteria for are at risk (Bamias and Boletis, 2008). This peculiar geo- BEN. Thereafter, an international panel of researchers has graphic distribution has remained constant since the 1950s. agreed on appropriate criteria for epidemiologic and clini- BEN has an onset of disease between 40 and 60 years cal studies on BEN (Stefanovic et al. 2007). of age and has a long latency period. Individuals of both During the “International Workshop on the Diag- genders are affected, with slight female predominance. nostic Criteria in BEN”, held in Brač, Croatia, in 2008, The disease occurs in adults, but not in children (Grollman and at a meeting organised in 2012 in Skopje, Macedo- 2013). BEN frequently results in terminal kidney failure, nia, novel criteria were evaluated and used for prepara- and it has been estimated that ~100,000 individuals are at tion of up-dated recommendations (KDIGO 2013). The risk, while ~25,000 have the disease (Pavlovic 2013). consensus was targeted to provide recommendations for The pathology of BEN has been reviewed in numerous the screening, diagnosis and therapy of patients suffer- reports (Bamias and Boletis 2008; Jankovic et al. 2009; ing from BEN (Jelakovic et al. 2014). A recent study by Jelakovic et al. 2014; Pavlovic 2013; Schiller et al. 2008; Dika et al. (2014) evaluated the diagnostic significance Wernerson et al. 2014). The pathology of BEN shares of the variables previously proposed to unify the diag- similarities with tubulointerstitial renal diseases and is nostic criteria of BEN, but also included new criteria. characterised by progressive kidney atrophy and sclerosis In the study patient subgroups, no statistical differences (Pavlovic 2013). Histologically, BEN is characterised by in haemoglobin level, leucine aminopeptidase in urine extensive hypocellular interstitial fibrosis associated with and active urinary levels of transforming growth factor β tubular atrophy. Glomerular and vascular lesions are asso- were found in the BEN diseased group when compared ciated with periglomerular fibrosis, glomerular lesions, to other subgroups. Kidney length and parenchyma thick- including ischaemic, microcystic, obsolescent glomeruli, ness, α1-microglobulinuria and
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