title: Chronic dietary exposure to aristolochic acid and kidney function in native farmers from a Croatian endemic area and Bosnian immigrants.
abstract: OBJECTIVE
  Improvements in agricultural practices in Croatia have reduced exposure to consumption of aristolochic acid-contaminated flour and development of endemic (Balkan) nephropathy. Therefore, it was hypothesized that Bosnian immigrants who settled in an endemic area in Croatia 15-30 years ago would be at lower risk of developing endemic nephropathy because of reduced exposure to aristolochic acid. To test this hypothesis, past and present exposure to aristolochic acid, proximal tubule damage as a hallmark of endemic nephropathy, and prevalence of CKD in Bosnian immigrants were analyzed.
  
  
  METHODS
  In this cross-sectional observational study from 2005 to 2010, 2161 farmers were divided into groups: indigenous inhabitants from endemic nephropathy and nonendemic nephropathy villages and Bosnian immigrants; α-1 microglobulin-to-creatinine ratio >31.5 mg/g and eGFR<60 ml/min per 1.73 m(2) were considered to be abnormal.
  
  
  RESULTS
  CKD and proximal tubule damage prevalence was significantly lower in Bosnian immigrants than inhabitants of endemic nephropathy villages (6.9% versus 16.6%; P<0.001; 1.3% versus 7.3%; P=0.003, respectively); 20 years ago, Bosnian immigrants observed fewer Aristolochia clematitis in cultivated fields (41.9% versus 67.8%) and fewer seeds among wheat seeds (6.1% versus 35.6%) and ate more purchased than homemade bread compared with Croatian farmers from endemic nephropathy villages (38.5% versus 14.8%, P<0.001). Both Croatian farmers and Bosnian immigrants observe significantly fewer Aristolochia plants growing in their fields compared with 15-30 years ago. Prior aristolochic acid exposure was associated with proximal tubule damage (odds ratio, 1.64; 95% confidence interval, 1.04 to 2.58; P=0.02), whereas present exposure was not (odds ratio, 1.31; 95% confidence interval, 0.75 to 2.30; P=0.33). Furthermore, immigrant status was an independent negative predictor of proximal tubule damage (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.86; P=0.02).
  
  
  CONCLUSIONS
  Bosnian immigrants and autochthonous Croats residing in endemic areas are exposed significantly less to ingestion of aristolochic acid than in the past. The prevalence of endemic nephropathy and its associated urothelial cancers is predicted to decrease over time.
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Bojan
authors.initials: B
authors.lastname: Jelaković
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and ivemedex@yahoo.com.
authors.forename: Ivana
authors.initials: I
authors.lastname: Vuković Lela
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Karanović
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Živka
authors.initials: Ž
authors.lastname: Dika
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Jelena
authors.initials: J
authors.lastname: Kos
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Dickman
authors.affiliation: Faculty for Natural Sciences, University of Zagreb, Zagreb, Croatia;
authors.forename: Maja
authors.initials: M
authors.lastname: Šekoranja
authors.affiliation: National Institute for Public Health, Zagreb, Croatia;
authors.forename: Tamara
authors.initials: T
authors.lastname: Poljičanin
authors.affiliation: Cytology Unit, Slavonski Brod, Croatia;
authors.forename: Maja
authors.initials: M
authors.lastname: Mišić
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Vedran
authors.initials: V
authors.lastname: Premužić
authors.affiliation: Outpatient Clinic Bebrina, Bebrina, Croatia;
authors.forename: Mirta
authors.initials: M
authors.lastname: Abramović
authors.affiliation: Outpatient Clinic Slavonski, Kobaš, Croatia;
authors.forename: Vesna
authors.initials: V
authors.lastname: Matijević
authors.affiliation: Institute for Public Health County Brodsko-Posavska, Slavonski Brod, Croatia;
authors.forename: Marica
authors.initials: M
authors.lastname: Miletić Medved
authors.affiliation: Institute for Public Health County Brodsko-Posavska, Slavonski Brod, Croatia;
authors.forename: Ante
authors.initials: A
authors.lastname: Cvitković
authors.affiliation: Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California, Irvine, Irvine, CA; and.
authors.forename: Karen
authors.initials: K
authors.lastname: Edwards
authors.affiliation: Clinical Laboratory Diagnostics, School of Medicine, University of Zagreb, University Hospital Center Zagreb, Zagreb, Croatia;
authors.forename: Mirjana
authors.initials: M
authors.lastname: Fuček
authors.affiliation: General Hospital, "Josip Benčević", Department of Internal Medicine, Dialysis Unit.
authors.forename: Ninoslav
authors.initials: N
authors.lastname: Leko
authors.affiliation: General Hospital, "Josip Benčević", Department of Internal Medicine, Dialysis Unit.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Teskera
authors.affiliation: Departments of Nephrology, Hypertension, Dialysis and Transplantation and.
authors.forename: Mario
authors.initials: M
authors.lastname: Laganović
authors.affiliation: Clinical Laboratory Diagnostics, School of Medicine, University of Zagreb, University Hospital Center Zagreb, Zagreb, Croatia;
authors.forename: Dubravka
authors.initials: D
authors.lastname: Čvorišćec
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York.
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Grollman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000382:Agricultural Workers' Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000208:ethnology / Q000503:physiopathology / Q000517:prevention & control; D000383:Agriculture; D000510:Alpha-Globulins / Q000652:urine; D034341:Aristolochic Acids / Q000009:adverse effects*; D001449:Balkan Nephropathy / Q000139:chemically induced* / Q000175:diagnosis / Q000208:ethnology / Q000503:physiopathology / Q000517:prevention & control; D015415:Biomarkers / Q000097:blood / Q000652:urine; D017522:Bosnia and Herzegovina / Q000208:ethnology; D003404:Creatinine / Q000097:blood / Q000652:urine; D017523:Croatia / Q000453:epidemiology; D003430:Cross-Sectional Studies; D004032:Diet / Q000009:adverse effects*; D054242:Emigrants and Immigrants; D005260:Female; D005506:Food Contamination; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016273:Occupational Exposure / Q000009:adverse effects* / Q000517:prevention & control; D016017:Odds Ratio; D015995:Prevalence; D012111:Residence Characteristics; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
chemical_list: D000510:Alpha-Globulins; D034341:Aristolochic Acids; D015415:Biomarkers; C016001:alpha-1-microglobulin; C000228:aristolochic acid I; D003404:Creatinine
keywords: CKD; albuminuria; interstitial fibrosis; proximal tubule