Critical evaluation of environmental exposure agents suspected in the etiology of Balkan endemic nephropathy.

Balkan endemic nephropathy (BEN), a kidney disease that occurs in rural villages in Bosnia, Bulgaria, Croatia, Romania, and Serbia, is thought to be linked to an environmental toxin. The authors review literature on proposed environmental exposure agents, report the results of field sampling and analysis studies to evaluate potentials for exposure to proposed agents, and propose criteria for future testing. They used these criteria to evaluate the evidence for suggested hypotheses, concluding that several proposed agents can be eliminated or considered unlikely based on apparent inconsistencies between clinical or epidemiologic evidence related to BEN and toxicologic or exposure evidence related to the agents. Mycotoxins and aristolochic acid are the primary targets of current toxicologic investigations, and while the evidence on exposures for both is potentially consistent, it is insufficient.

Nitrogen species in drinking water indicate potential exposure pathway for Balkan Endemic Nephropathy.

This study explored two hypotheses relating elevated concentrations of nitrogen species in drinking water and the disease Balkan Endemic Nephropathy (BEN). Drinking water samples were collected from a variety of water supplies in both endemic and non-endemic villages in the Vratza and Montana districts of Bulgaria. The majority of well water samples exceeded US drinking water standards for nitrate + nitrite. No statistically significant difference was observed for any of the nitrogen species between villages classified as endemic and non-endemic. Other constituents (sodium, potassium and chloride) known to be indicators of anthropogenic pollution were also found at elevated concentrations and all followed the order wells > springs > taps. This ordering coincides with the proximity of human influences to the water sources. Our results clearly establish an exposure pathway between anthropogenic activity and drinking water supplies, suggesting that the causative agent for BEN could result from surface contamination.

Balkan endemic nephropathy and genetic variants of glutathione S-transferases.

BACKGROUND: Balkan endemic nephropathy (BEN) is a non-inflammatory, chronic, slow progressing kidney disease, frequently associated with urinary tract tumors. BEN displays familial clustering without an apparent Mendelian inheritance pattern. It has been suggested that environmental toxicants damage urothelial cells in genetically susceptible individuals, which could be the cause of BEN. The metabolism of some substrates that are mediated by glutathione S-transferases (GST), which are polymorphic enzymes, results in nephrotoxic products. To evaluate whether GST genetic heterogeneity could be involved in BEN, we launched a case-control study concerning the association of the most common polymorphic GST variants with BEN. METHODS: DNA was extracted from venous blood samples from 54 unrelated BEN patients and 104 controls inhabiting the same endemic region. GSTM1 and GSTT1 null deletions were identified simultaneously by a triplex polymerase chain reaction (PCR) procedure, and GSTP1 polymorphism was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) using Alw261. RESULTS: Carriers of at least one GSTM1 wild type allele (wt-allele) were more prevalent among BEN patients compared to controls (chi2=7.92, p=0.005). The GSTT1 and GSTP1 genotype distributions did not demonstrate statistically significant differences between the groups. The carriers of at least one GSTM1 wt-allele among BEN patients were more prevalent in comparison with controls when the GSTM1 genotypes were combined in pairs with all GSTT1 (chi2=9.52, p=0.023) and GSTP1 (chi2=11.92, p=0.036) genotypes. The combined genotype distributions of the three GST genes studied among BEN patients and controls showed that the frequency of carriers of at least one GSTM1 wt-allele among BEN patients was higher or at least equal to the corresponding frequency among controls in all triple combinations. However, this difference did not reach statistical significance (chi2=14.06, p=0.170). CONCLUSIONS: GSTM1 wt-allele associates with BEN. The significantly lower prevalence of the GSTM1 deletion homozygotes among BEN patients suggests that individuals bearing the GSTM1 null genotype could be better protected.