European Journal of Epidemiology

, Volume 14, Issue 4, pp 389–394 | Cite as

Etiology of Balkan endemic nephropathy: A multifactorial disease?

  • Draga Toncheva
  • Tzvetan Dimitrov
  • Stiliana Stojanova


Balkan endemic nephropathy (BEN) is of great clinical importance in the restricted areas of Bulgaria, Rumania, Croatia, Serbia, Bosnia and Herzegovina. So far, studies on the etiological factors for BEN have not discovered any single environmental causative agent of this puzzling disease. These data reject the possibility of a purely environmental causation of BEN. The pattern of BEN transmission in the risk families is not typical for single gene disorders. Extensive epidemiological and genetic studies disclose characteristics of multifactorial (polygenic) inheritance of BEN. The evidences of 'familial tendency', variation of the risk for BEN depending on the number of sick parents and the degree of relatedness; the development of BEN in individuals from at-risk families who were born in non-endemic areas; the data that disease is not found in the gypsy population and the expressions of 3q25 cytogenetic marker suggest that the genetic factors play an important role as causative factors in BEN development. The possible impact of environmental triggers on individuals genetically predisposed to BEN could be supposed by the following data: the cytogenetic results of the increased frequency of folate sensitive Fra sites, spontaneous or radiation-induced aberrations in several bands in BEN patients, the data from the detailed analysis of breaks in BEN patients and controls that generate structural chromosome aberrations; the occurrence of BEN in immigrants. Genetical epidemiological approaches to etiology and prevention of BEN are proposed. The predisposing genes for BEN could be genes localized in a region between 3q25-3q26; transforming growth factor-β (TGF-β), genetic heterogeneity of xenobiotic-metabolizing enzymes; defects in the host's immune system. The predisposing genes for BEN patients with urinary tract tumors could be germline mutations in tumor suppressor genes and acquired somatic mutations in oncogenes.

Balkan endemic nephropathy Genetic epidemiology Genetic factors Multifactorial disease Predisposing genes 3q marker 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Kischew S. Uber die Fragen der Tumoren in Nierenbecken und in Harnleiter bei den Kranken mit endemischer Nephritis aus dem Krcise Vratza. Acta Urol Belg 1958; 26: 260–268.PubMedGoogle Scholar
  2. 2.
    Puchlev A, Astrug A, Popov N, Dotchev D. Clinical studies of endemic nephropathy. In: Puchlev A (ed), Endemic nephropathy in Bulgaria. Sofia: Med Physk, 1960: 7–71.Google Scholar
  3. 3.
    Petrinska S. Clinical studies of endemic nephropathy. In: Puchlev A (ed), Endemic nephropathy in Bulgaria. Sofia: Med Physk, 1960: 72–90.Google Scholar
  4. 4.
    Goldberg M. Balkan nephropathy. In: Wijngaarden JB, Smith LH Jr (eds), Cecil textbook of medicine. Philadelphia, London, etc.: W.B. Saunders Cy, 1985: 590.Google Scholar
  5. 5.
    Drukker W, Schwarz A, Vanherweghem JL. Analgesic nephropathy: An underestimated cause of end-stage renal disease. Int J Artif Organs 1986; 9: 219–246.PubMedGoogle Scholar
  6. 6.
    Bozic Z, Duancic V, Belicza M, Kraus O, Skljarov I. Balkan endemic nephropathy: Still a mysterious disease. Eur J Epidemiol 1995; 11: 235–238.PubMedGoogle Scholar
  7. 7.
    Ceovic S, Hrabar A, Saric M. Epidemiology of Balkan endemic nephropathy. Food Chem Toxicol 1992; 30: 183–188.CrossRefPubMedGoogle Scholar
  8. 8.
    Radovanovic Z. Aetiology of Balkan nephropathy: A reappraisal after 30 years. Eur J Epidemiol 1989; 5: 372–377.PubMedGoogle Scholar
  9. 9.
    Hrabar A, Ceovic S, Aleraj B, Cvoriscec D, Hall PW III. Relationship of anemia to Balkan endemic nephropathy. Kidney Int 1992; 40(Suppl 34): S44–S45.Google Scholar
  10. 10.
    Cosyns JP, Jadoul M, Squifflet JP, De Plaeu JF, Ferluga D, Ypersele de Strihou D. Chinese herbs nephropathy: A clue to Balkan endemic nephropathy. Kidney Int 1994; 45: 1680–1688.PubMedGoogle Scholar
  11. 11.
    Castegnaro M, Chernozemsky IN, Heitanen E, Bartsch H. Are mycotoxins risk factors for endemic nephropathy and associated urothelial cancers? Arch Geschwulstforsch 1990; 60: 295–303.PubMedGoogle Scholar
  12. 12.
    Bach PH, Gregg NJ, Delacruz L. Relevance of a rat model of papillary necrosis and upper urothelial carcinoma in understanding the role of ochratoxin A in Balkan endemic nephropathy and its associated carcinoma. Food Chem Toxicol 1992; 30: 205–211.CrossRefPubMedGoogle Scholar
  13. 13.
    Castegnaro M, Maru V, Petkova-Bocharova T, Nikolov I, Bartsch H. Concentrations of ochratoxin A in the urine of endemic nephropathy patients and controls in Bulgaria: Lack of detection of 4-hydroxy-ochratoxin A. IARC Scientific Publications 1991; 115: 165–169.Google Scholar
  14. 14.
    Fuchs R, Radic B. Endemic nephropathy. In: Cvoriscec D, Ceovic S, Rukavina A (eds), Endemic nephropathy in Croatia. Academia Croatica Scientiarum Medicarum, 1996: 31–38.Google Scholar
  15. 15.
    Astrug A, Parsons V. Neutron-activation analysis of some trace elements with endemic nephropathy. Proceedings of the 3rd Symposium on Endemic Nephropathy, Nis, 1977: 174–177.Google Scholar
  16. 16.
    Maksimovic Z. Trace element deficiency and Balkan endemic nephropathy. Proceedings of the 6th Symposium on Endemic Nephropathy, Nis, 1987: 43–47.Google Scholar
  17. 17.
    Čeović S, Hrabar A, Radonić M. An etiological approach to Balkan endemic nephropathy based on the investigation of two genetically different populations. Nephron 1985; 40: 175–179.PubMedGoogle Scholar
  18. 18.
    Dimitrov T. Balkan endemic nephropathy. Sofia: Ben, 1983: 191.Google Scholar
  19. 19.
    Kraus N. Studien uber die endemische Nephrozirrhose der Balkanhalbinscl. Zeitschrift fur ärztliche Forbildung 1996; 60: 829–834.Google Scholar
  20. 20.
    Birtasevic B, Vukovic D, Drndarevic D, Seguljev Z, Obradovic M, Pokorni D, Cobeljic M, Stoljic P, Stefanovic S, Stankovic A, Bojanic N, Spasic P. Endemic (Balkan) nephropathy as a natural foci infection? Military Sanit Revue 1983; 40: 319–324.Google Scholar
  21. 21.
    Apostolov K, Spasic P, Bojanic N. Evidence of a viral atiology in endemic (Balkan) nephropathy. Lancet 1975; 2: 1271–1273.CrossRefPubMedGoogle Scholar
  22. 22.
    Aleraj B. A study of the viral etiology of endemic nephropathy. In: Cvoriscec D, Ceovic S, Rukavina A (eds), Endemic nephropathy in Croatia. Zagreb: Academia Croatia Scientiarum Medicarum, 1996.Google Scholar
  23. 23.
    Mihailov T. Clinico-genealogical investigations on Balkan endemic nephropathy in Bulgaria [Dissertation]. Sophia, Bulgaria: University of Sofia, 1979.Google Scholar
  24. 24.
    Stojanova S. Genetic study on Balkan endemic nephropathy. Graduation work, Sofia, 1991: 1–75.Google Scholar
  25. 25.
    Toncheva D, Dimitrov T, Tzoneva M. Cytogenetic studies in Balkan endemic nephropathy. Nephron 1988; 48: 18–21.PubMedGoogle Scholar
  26. 26.
    Toncheva D, Dimitrov T. Genetic predisposition to Balkan endemic nephropathy. Nephron 1996; 72: 564–569.PubMedGoogle Scholar
  27. 27.
    Toncheva D, Gergov T, Tzoneva M, Bouchakliev Z. Spontaneous and induced chromosome aberrations in Balkan endemic nephropathy. Kidney Int 1991; 34: S97–S101.Google Scholar
  28. 28.
    Toncheva D, Dimitrov T. Balkan endemic nephropathy and cancer breakpoints. International Symposium on Etiopathogenesis and Early Diagnosis of Endemic Nephropathy, Zagreb, Nov. 7–9, 1996. Cancer Detection and Prevention (in press).Google Scholar
  29. 29.
    Manolov G, et al. Chromosomal alterations in lymphocytes of patients with BEN and of healthy individuals after incubation in vitro with OA. IARC Sci Publ 1991; 115: 267–272.Google Scholar
  30. 30.
    Nikolov I, Chernozemsky I, Idle J. Genetic predisposition to Balkan endemic nephropathy: Ability to hydroxylate debrisoquine as a host factor. In: Castegnaro M, Plestina R, Dirheimer G, Chernozemsky G, Bartsch H (eds), Mycotoxins, endemic nephropathy and urinary tract tumours. Lyon: International Agency for Research on Cancer, 1991: 289–296.Google Scholar
  31. 31.
    Soderkvis P, Axelson O. On the use of molecular biology data in occupational and environmental epidemiology. J Occup Environ Med 1995; 37: 84–90.PubMedGoogle Scholar
  32. 32.
    Kluwe W, Abdo K, Huff J. Chronic kidney disease and organic chemical exposures: Evaluations of causal relationships in humans and experimental animals. Fundam Appl Toxicol 1984; 4: 889–901.CrossRefPubMedGoogle Scholar
  33. 33.
    Smith D, Glover T, Gemmill R, Drabkin H, O'Connell P, Naylo S. Report of the fifth international workshop on human chromosome 3 mapping 1994. Cytogenet Cell Genet 1995; 68: 126–143.Google Scholar
  34. 34.
    Kruzelock R, Murphy E, Strong L, Naylor S, Hansen M. Localization of a novel tumor suppressor locus on human chromosome 3q important in osteosarcoma tumorigenesis. Cancer Res 1997; 57: 106–109.PubMedGoogle Scholar
  35. 35.
    Border W, Noble N. Transforming growth factor β in tissue fibrosis. N Engl J Med 1994; 331: 1286–1292.CrossRefPubMedGoogle Scholar
  36. 36.
    Sharma K, Ziyadeh F. The transforming growth factor-beta system and the kidney. Semin Nephrol 1993; 13: 116–128.PubMedGoogle Scholar
  37. 37.
    Frebourg T, Barbier N, Yan YX, Garber JE, Dreyfus M, Fraumeni J, Li F, Friend S. Germ line p53 mutations in 15 families with Li Fraumeni syndrome. Am J Hum Genet 1995; 56: 608–615.PubMedGoogle Scholar
  38. 38.
    Hamelin R, Barichard F, Henry I, Junien C, Thomas G. Single base pair germ line deletion in the p53 gene in a cancer predisposed family. Hum Genet 1994; 94: 88–90.PubMedGoogle Scholar
  39. 39.
    Birch J, Harley A, Tricker K, Prosser J, Condie A, Kelsey A, Harris M, Jones P, Binchy A, Crowther D, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res 1994; 54: 1298–1304.PubMedGoogle Scholar
  40. 40.
    Soussi T, Leblanc T, Baruchel A, Schaison G. Germline mutations of the p53 tumor suppressor gene in cancer prone families: A review. Nouv Rev Fr Hematol 1993; 35: 333–336.Google Scholar
  41. 41.
    Law J, Strong L, Chidambaram A, Ferrell R. A germ line mutations in exon 5 of the p53 gene in an extended cancer family. Cancer Res 1991; 51: 6385–6387.PubMedGoogle Scholar
  42. 42.
    Cooper M, Haluschak J, Johnson D, Schwartz S, Morrison L, Lippa M, Hatzivassiliou G, Tan J. p53 mutations in bladder carcinoma cell lines. Oncol Res 1994; 6: 569–579.PubMedGoogle Scholar
  43. 43.
    Habuchi T, Kinoshita H, Yamada H, Kakehi &, Ogawa O, Wu WJ, Takahashi R, Sugiyama T, Yoshida O. Oncogene amplification in urothelial cancers with p53 gene mutation of MDM2 amplification. Japan J Natl Cancer Inst 1994; 86: 1331–1335.Google Scholar
  44. 44.
    Bell D. Use of pharmacogenetics in cancer epidemiology studies and cancer risk assessment. TBC's Third Annual Conference on Pharmacogenetics, Washington, 1997.Google Scholar
  45. 45.
    Lipkowitz M, Klotman M, Bruggeman L, Nicklin P, Hanss B, Rappoport J, Klotman P. Molecular therapy for renal diseases. Am J Kidney Dis 1996; 28: 475–492.PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Draga Toncheva
    • 1
  • Tzvetan Dimitrov
    • 2
  • Stiliana Stojanova
    • 1
  1. 1.Department of Medical GeneticsMedical University, Medical Faculty-SofiaSofiaBulgaria
  2. 2.Department of NephrologyMedical University, Medical Faculty-SofiaSofiaBulgaria

Personalised recommendations