engleski

Aristolactam-DNA adducts anre a biomarket of environmental exposure to aristolochic acid out of established endemice nephropathy rural villages.

INTRODUCTION AND AIMS: Endemic nephropathy (EN) which was found in strict geographical areas in Balkan region is an environmental form of aristolochic acid nephropathy (AAN). Recently, we proved that the presence of aristolactam DNA adducts is the firm evidence for the exposure to aristolochic acid (AA), the confirmed etiological agent of EN i.e. AAN. Upper urothelial cancers (UUC) which occur in 50% of EN patients can be a solitary manifestation of exposure to AA. It has not been resolved why EN should be restricted only to several limited rural areas and it was questioned whether EN might unrecognized occur in villages out of established endemic focuses. Our aim was to confirm occurrence of this sporadic form of EN in villagers from Croatia and Bosnia analyzing the presence of aristolactam DNA adducts in kidney cortex of patients with UUC. METHODS: In this retrospective study (2005-2010), the samples of 72 UUC from 69 patients (27 men, 42 women) residing from Croatia and Bosnia were analyzed. The data on medical history, place of birth and residence as well as laboratory data were taken from hospital medical records. The histopathological data were reviewed by two pathologists. 46 patients had available specimens of renal cortex, and aristolactam (AL)-DNA adducts were quantified by (32)P- postlabeling and the adduct was confirmed by mass spectrometry. RESULTS: Out of 72 tumors, 37 and 35 cases were from EN and non-EN areas, respectively. Mean age of patients was 72 (41-84), no statistical difference was found between EN and non-EN patients (p=0.2398). Also no significant differences were found in tumor grade (EN (N): LG 9, HG 26 ; non-EN (N): LG 14, HG 18, v2=2.412 ; p=0.12) or tumor recurrence rate (EN vs. non-EN 16.2% vs.22.9%, v2=0.5064 ; p=0.47), as well as in patients’ kidney function (eGFR- MDRD) at the time of surgery (EN vs. non-EN 41.1 vs. 53.1 ml/min/1.73m2 ; p=0.2044). There were more women within the EN group (v2=3.9679 ; p=0.046) while hemoglobin values were higher in non-EN group (110 vs. 123 g/l ; p=0.0391). Positive AL-DNA adducts were found in renal cortex of 63% (29/ 46) patients with UUCs. As expected it was found in 18/28 patients from EN areas but importantly also in 11/18 patients from non- endemic villages. CONCLUSIONS: Based on the presence of aristolactam DNA adducts in 63% analyzed samples it can be concluded that aristolochic acid is the most frequent cause of UUC in this cohort of peasants from Croatia and Bosnia. Finding of aristolactam DNA adducts in patients residing out of established EN villages is the first molecular evidence for occurrence of EN i.e. AAN much broader than previously considered. This is an important alert for nephrologists, urologist and public health authorities which are taking care of villagers from all world regions where plants of Aristolochia genus are growing.

endemic naphropathy ; aristolochic acid

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