Balkan endemic nephropathy: a need for novel aetiological approaches

Abstract

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.

Limitations and plausibility of the Pliocene lignite hypothesis in explaining the etiology of Balkan endemic nephropathy

“…6 Provided that the necessary hydrogeologic conditions for leaching and transportation of the organic compounds from the deposits to wells and springs have been met, a BENlike kidney disease may still exist unrecognized, e.g., in developed countries due to population mobility, and/or too small an area affected (such as coal stored next to a power plant 30 ), and in undeveloped areas, i.e., Burma and rural China, due to inadequacies in the medical infrastructure for correct diagnoses. 6 Furthermore, as more data becomes available, more possible links may be supported, e.g., an interstitial nephropathy similar to BEN has been described in Greece; 22 in Louisiana and Wyoming, USA, kidney disease and renal pelvic cancer may be associated with coal deposits, including lignites; 58,75 and in Texas, USA 76 and northern Portugal, 77 renal disease may also be associated with lignites. Thus, the restricted disease distribution of BEN to the Balkans may be due to the distinct organic compound composition of the regional organic-rich leachable rocks and sediment (including, of course, Pliocene lignites), which are unique with respect to petrological and organic geochemistry reflecting differences in the for instance, peat forming vegetation and paleoenvironment as a result of the limiting paleogeographic coal-forming conditions in the Tertiary swamps during the Pliocene, 27 coupled with the right hydrological, demographical, and medical infrastructure conditions.…”

“…44,[52][53][54] However, ochratoxin A contamination has been found in both endemic and nonendemic regions, 22,55,56 nonaffected households, 57 and in Romania, no ochratoxin A or its degradation products were detected in the urine of BEN patients, 58 raising doubts about its role in the etiology of the disease. Likewise, Aristolochia plants are ubiquitous, 24 and Aristolochia contamination has occurred in nonendemic areas of BEN affected countries.…”

“…22 For example, in Vreoci in the Kolubara region, Serbia, new BEN patients were found only in families in which the disease had already been recorded. 66 Plus, along with BEN patients, hyper-beta 2 -microglobulinuria 90,91 and increased urinary albumin excretion [90][91][92][93] have been observed in family members of BEN patients.…”

“…5 Transplantation is usually not an option, 6 and typically 50% of patients have died within 2 years of diagnosis. 7 Of the many hypotheses that have been proposed for the etiology of BEN, [8][9][10][11][12][13][14][15][16][17][18] evidence from many studies favors the involvement of an environmental factor(s) in the etiology of the disease, 1,[19][20][21][22][23][24][25][26] for example, exposure to organic compounds from Pliocene lignite coal deposits. The Pliocene lignite hypothesis posits that BEN is caused by long-term exposure to low concentrations of toxic organic compounds leaching into drinking water, that is used almost exclusively by the population, via groundwater from Pliocene lignites found in the vicinity of endemic settlements.…”

Review of literature on chronic kidney disease of unknown etiology (CKDu) in Sri Lanka

“…The Balkan endemic nephropathy (BEN) has been described as a chronic kidney disease prevalent among settlers along the tributaries of the Danube River in Serbia, Bosnia, Bulgaria and Romania (Stefanovic 1998). First described in 1957, BEN is a slowly progressive tubulo-interstitial disease leading to end-stage renal failure.…”