Balkan endemic nephropathy: a need for novel aetiological approaches.

Aetiology remains the main unanswered problem in Balkan endemic nephropathy (BEN) despite investigations into the roles of genetic factors, environmental agents and immune mechanisms. Evidence has accumulated that BEN is an environmentally-induced disease. Weathering of low-rank coals near to the villages where BEN is endemic produces water-soluble polycyclic aromatic hydrocarbons and aromatic amines, similar to metabolic products of acetaminophen that cause analgesic nephropathy. Many of these compounds are known to be carcinogenic and could also cause urothelial cancer. Genetic studies have supported genetic predisposition to BEN. The candidate genes have been localized to a region between 3q25 and 3q26, the 3q BEN marker being detected in both BEN patients and in some healthy relatives with initial morphological changes peculiar to BEN. Three bands with increased frequencies of spontaneous and induced aberrations contain oncogenes. The frequent association of BEN and urinary tract tumours (UTT) can be explained by the chromosomal hypothesis of oncogenesis. The results of molecular biological investigations will allow the identification of genetic markers of BEN, permitting early detection of BEN-predisposing mutations and identification of susceptible individuals who may be at risk of exposure to the environmental agents. An increased incidence of tumours of renal pelvis and ureter in patients with BEN and in population from endemic settlements has been observed. Familial clustering of the UTT was also reported. The frequency of urinary bladder tumours in BEN-endemic settlements is also increased compared with the non-endemic villages and cities. The geographic correlation between BEN and UTT supports the speculation that these diseases share a common aetiology.