Genetic predisposition to Balkan endemic nephropathy: ability to hydroxylate debrisoquine as a host risk factor

The objective of this study was to examine the association between efficiency of oxidative metabolism and risk for developing Balkan endemic nephropathy (BEN) and/or transitional-cell carcinoma of the urinary tract, using a case-control design controlling for age, gender and socioeconomic factors. Over 900 urine samples were taken from 646 subjects, divided into the following groups: healthy subjects from areas with no BEN; healthy subjects from villages with BEN; subjects suspected of having BEN; and subjects with BEN and/or upper urinary tract tumours (UUT). BEN patients and controls from the same villages were of similar age. The highest urinary recovery of debrisoquine was found among controls from areas with no BEN; recovery in BEN patients was only 50% of that in controls. The most interesting result is that BEN patients did not have impaired debrisoquine metabolism: subjects who metabolized less than 25% of the drug represented only 2.9% of BEN patients, 12.4% of controls from BEN villages and 12.7% of controls from outside the BEN area. The very poor metabolizers represented 1.0% of BEN patients and 4.8-5.8% of controls. the percentages of extensive metabolizers in the same groups were 86.3, 64.5 and 67.4%, respectively. The mean metabolic ratio rose progressively from BEN patients less than suspected BEN patients less than controls from BEN villages less than controls from non-BEN villages; the maximum metabolic ratios were 40, 51, 72 and 87, respectively. The cumulative distribution of the 8-h urinary debrisoquine metabolic ratios, presented as a normal probability plot, formed a discrete population with values over 10. The distribution among patients with BEN/UUT indicates a predominance of extensive debrisoquine hydroxylation and a lack of poor metabolizers. These results are consistent with the hypothesis that the efficiency of oxidative metabolism is greater in BEN patients and that it may be one of the key host factors determining predisposition to these diseases.