Balkan endemic nephropathy and associated urinary tract tumours: a review on aetiological causes and the potential role of mycotoxins

Abstract

A series of publications in the 1950s described a kidney disease in Bulgaria, the former Yugoslavia and Romania that became known as Balkan endemic nephropathy (BEN). The disease was qualified by World Health Organisation (WHO) experts as 'progressive and very gradually developing renal failure with insidious onset.... The last stage shows marked fibrosis...'. BEN is characterized by tubular degeneration, interstitial fibrosis and hyalinization of glomeruli accompanied by enzymuria and impaired renal function without nephrotic syndrome. Later, an association between BEN and tumours of the kidney pelvis and ureter was recognized, so that the problem of BEN became not only nephrological, but also oncological. There may also be an association with increased urinary bladder cancer incidence, although many confounding factors may interfere in the analysis of data for this organ. In view of the very intimate association between BEN and the urinary tract tumours (UTT), the term 'endemic uropathy' has been proposed. Several hypothesis concerning the aetiology of these diseases has been investigated, which include: predisposing genes factors, environmental factors (heavy metals, minerals, bacteria, leptospira, viruses, fungal toxins and, most recently, pliocene lignites). This paper reviews the different hypotheses about the aetiology of endemic uropathy and pays particular attention to the role of fungal toxins.

Is aristolochic acid a risk factor for Balkan endemic nephropathy‐associated urothelial cancer?

“…13 This hypothesis, however, has not yet received sufficient support. 11,12 Our findings here provide the first evidence that people living in endemic areas for BEN have been exposed to AA. Because many herbal remedies are used locally in these areas, 12 the cases reported here raises major concerns for public health.…”

“…Other contaminations may come from citrinin, another mycotoxin, which has also been found in food in endemic areas and showed a synergistic effect with OTA. 11 AAN patients have been exposed to high amounts of AA within a few months (Ϸ15-20 months) providing a reason for the rapid development of AAN and AAN-associated urothelial tumors (Ϸ2-6 years). 2,4,11,12 In contrast, people in endemic areas for BEN might have been exposed chronically to low amounts of AA over years, which might explain the slow development of BEN and BEN-associated urothelial malignancy.…”

Evaluation of the hypothesis that Balkan endemic nephropathy is caused by drinking water exposure to contaminants leaching from Pliocene coal deposits

“…Researchers seem to agree that BEN may result from prolonged exposure to one or more environmental toxicants acting alone or synergistically on genetically predisposed individuals/populations (Ganev and Petropoulos, 1999). Hypothesized environmental factors include exposure to: heavy metals (Wedeen, 1991), arsenic (Ganev and Petropoulos, 1999), dissolved nitrogen species (Radovanovic and Stefanovic, 1988), organic compounds leached from coal deposits (Feder et al, 1991), herbs containing aristolochic acid (Cosyns et al, 1994;Hranjec et al, 2005), mycotoxins (Dimitrov, 1960;Pfohl-Leszkowicz et al, 2002), and viruses (Kraus, 1996). Calcium, magnesium and selenium deficiencies in the diet have also been suggested, as this element is known to limit the damage from free radicals (Hoops and Feder, 1986;Maksimovic, 1987).…”

Human hepatic and renal microsomes, cytochromes P450 1A1/2, NADPH:Cytochrome P450 reductase and prostaglandin H synthase mediate the formation of aristolochic acid‐DNA adducts found in patients with urothelial cancer

“…7,8 Recently, a high prevalence of urothelial cancer was found in a large cohort of patients suffering from aristolochic acid nephropathy in Belgium 9,10 and a case with urothelial cancer has also been described in the United Kingdom. 11 It is also noteworthy that AA consumption may be a cause for the development of a similar type of fibrosis of the kidneys with malignant transformation of the urothelium, the Balkan endemic nephropathy, [12][13][14][15] which is widely found in certain areas of Rumania, Croatia, Bosnia, Serbia and Bulgaria along the Danube river basin. [12][13][14][15] This highlights the carcinogenic potential of AA in human beings.…”

“…11 It is also noteworthy that AA consumption may be a cause for the development of a similar type of fibrosis of the kidneys with malignant transformation of the urothelium, the Balkan endemic nephropathy, [12][13][14][15] which is widely found in certain areas of Rumania, Croatia, Bosnia, Serbia and Bulgaria along the Danube river basin. [12][13][14][15] This highlights the carcinogenic potential of AA in human beings. It is worth noting that herbal remedies containing species of the genus Aristolochia were recently classified as carcinogenic to humans by the International Agency for Research on Cancer.…”