Abstract
Balkan nephropathy (BN) has been a complete aetiological puzzle for many years. Intense research produced many controversial results, but also helped some clues to be traced. Thus, it became rather obvious that the disease is caused by environmental factors (though it may be, to some extent, genetically controlled). Among live agents, slow viruses are the only (and theoretically very attractive) possible cause of both BN and urothelial tumours, which occur frequently in BN endemic areas. Apart from occasional visualization of virus-like particles, other evidence supporting this hypothesis has been lacking. The role of biological products, particularly fungal toxins, needs to be further defined. An excess of any heavy metal or radioactive substance as a cause of BN is very unlikely indeed; however, a deficiency of a bio-essential element could not be ruled out. Many epidemiological data indicate that water might be a transmitter of the agent(s). A wide range of ions and minerals have been incriminated, but up to now most of the studies have provided negative or inconclusive results. Organic compounds in well water have never been sufficiently considered. Another ignored area are unstable and, particularly, photosensitive substances. Fertilizers, pesticides, analgesics, local herbs and teas have no causal relation to BN.
Key words: Balkan nephropathy, Urothelial tumours, Aetiology
References
- 1.Akhmeteli M.A. Proc. 2nd Int. Symp. End. Nephr. Sofia: Bulgar. Acad. Sci. Press; 1974. Epidemiology of endemic nephropathy; pp. 19–23. [Google Scholar]
- 4.Apostolov K., Spasic P., Bojanic N. Evidence of a viral etiology in endemic (Balkan) nephropathy. Lancet. 1975;2:1271–1273. doi: 10.1016/S0140-6736(75)90609-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Birtasevic B., Vukovic B., Drndarevic D., Seguljev Z., Obradovic M., Pokorni D., Cobeljic M., Stojic P., Stefanovic S., Stankovic A., Bojanic N., Spasic P. Endemic (Balkan) nephropathy as a natural foci infection. Military Sanit. Revue. 1983;40:319–324. [PubMed] [Google Scholar]
- 4.Bruckner I., Raileanu-Motoiu I., Nichifor E. Cytogenetic studies in a population with Balkan nephropathy. Rev. Roum. Med. Int. 1978;15:219. [Google Scholar]
- 5.Bulic F. The possible role of genetic factors in the eatiology of the Balkan nephropathy. In: Wolstenholme G.E.W., Knight J., editors. The Balkan Nephropathy. London: Churchill; 1967. pp. 17–22. [Google Scholar]
- 6.Bull. Acad. Serbe Sci. Arts, T. 59, Cl. sci. med. 12, Belgrade, 1980.
- 7.Ceovic S. (1971): Contribution to the epidemiology of endemic nephropathy in Brodska Posavina. M. Sc. Dissertation. University of Zagreb.
- 8.Danilovic Y. Chronic nephritis due to ingestion of lead-contaminated flour. Brit. Med. J. 1958;1:27–28. doi: 10.1136/bmj.1.5061.27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Edmunds W.M., Miles D.L. Report No. WD/ST/82/11 of British Council supported visit to Yugoslavia. Wallinford, U.K.: Institute of Geochemical Sciences; 1963. Balkan endemic nephropathy. [Google Scholar]
- 10.Fajgelj A., Popovic N., Durovic N. Cadmium as a possible etiological factor of endemic nephropathy. Med. Arh. 1975;29:241–247. [PubMed] [Google Scholar]
- 11.Gaon J., Griggs R.C., Vasiljevic M., Alibegovic S. Investigation of chronic endemic nephropathy in Yugoslavia. I. Lead as possible etiologic agent. Acta Med. Yugosl. 1962;16:347–353. [Google Scholar]
- 12.Georgescu L., Litvac B., Diosi P., Plavosin L., Hergoz G. Viruses (Balkan) nephrophathy. Lancet. 1976;2:1086. doi: 10.1016/S0140-6736(76)92274-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hall P.W. (1981): A review of the role of beta-2-microglobulin in investigations of Balkan nephropathy and papillary transitional cell tumors. Proc. 1st Congress of the Yugoslav nephrologists. -Belgrade, pp. 90–94.
- 14.Hall P.W. (1982): Endemic Balkan nephropathy. In: Porter G. (ed.) Nephrotoxic Mechanisms of Drugs and Environmental Toxins. - Plenum Publ. Corp., pp. 227–240.
- 15.Hall P.W., Dammin G. Balkan nephropathy. Nephron. 1978;22:281–300. doi: 10.1159/000181465. [DOI] [PubMed] [Google Scholar]
- 16.Hrisoho D. (1967): Inheritance as an etiopathogenetic factor of the endemic intestitial nephropathy. - Proc. 1st Symp. End. Nephr., University of Nis. 75-79.
- 17.Hult K., Plestina R., Habazin-Novak Y., Radic B., Ceovic S. Ochratoxin A in human blood and Balkan endemic nephropathy. Arch. Toxicol. 1982;51:313–321. [Google Scholar]
- 18.Ivic M. The problem of etiology of endemic nephropathy. Acta Fac. Med. Naiss. 1970;1:29–38. [Google Scholar]
- 19.Karamikhailova E., Nikolov K., Doichinova K., Mikhailova V. On the radioactivity of the water sources in the villages affected by endemic nephritis. In: Puchlev A., editor. Endemic Nephritis in Bulgaria. Sofia: Medizina i Fizkultura; 1960. [Google Scholar]
- 20.Kraus N. Studien uber die endemische Nephrozirrhose der Balkanhalbinsel. Zeitschrift fur arztliche Fortbildung. 1966;60:829–834. [PubMed] [Google Scholar]
- 21.Krogh P. Mycotoxic nephropathy in swine. In: Wyllie T.D., Morehouse L.G., editors. Mycotoxic fungi, mycotoxins, mycotoxicoses, vol. 2. New York: Marcel Dekker; 1978. pp. 236–256. [Google Scholar]
- 22.Krogh P. Causal associations of mycotoxic nephropathy. Acta Path. Microbiol. Scand. Sect. A. 1978;269:1–28. [PubMed] [Google Scholar]
- 23.Levi-Jovovic E., Milojevic Lj., Milosavljevic R., Velickova G., Stefanovic V., Strahinjic S., Pavlovic N.M., Djordjevic M., Vukomanovic M. and Milosevic B. (1983): Complement-fixing antibodies for some viruses in patients with endemic nephropathy. - Proc. 5th Symp. End. (Balkan) Nephr., Nis., pp. 1–5.
- 24.Maksimovic Z. and Radovanovic Z. (1984): Balkan endemic nephropathy in Yugoslavia and geochemical studies. In: Hemphill D.D. (ed.). Trace Elements in Environmental Health. - 18, University of Missouri, pp. 230–236.
- 25.Martinicic A. Die toxische Wirkung von Aristolochia clematitis auf die Niere des Pferdes. Zbl. Allg. Pathol. Path. Anat. 1956;94:402. [Google Scholar]
- 26.Mengs U., Lang W., Poch J.A. The carcinogenic action of aristolochic acid in rats. Arch. Toxicol. 1982;51:107–119. [Google Scholar]
- 27.Mihailov T. (1979): Clinico-genealogical investigations on Balkan endemic nephropathy in Bulgaria. - Ph. D. Thesis, University of Sofia.
- 28.Milosevic M.B. Proc. 1st. Intern. Symp. End. Nephr. Sofia: Bulg. Acad. Sci. Press.; 1965. Endemic nephropathy in the middle of the Morava district; pp. 77–81. [Google Scholar]
- 29.Minev M., Mikhaylov T., Kastelan A., Nyulassy S., Menzel G. HLA system and Balkan endemic nephropathy. Tissue Antigens. 1978;11:50. doi: 10.1111/j.1399-0039.1978.tb01222.x. [DOI] [PubMed] [Google Scholar]
- 30.Naumovic T., Velimirovic D., Danilovic V. Proc. 2nd Int. Symp. End. Nephr. Sofia: Bulgar. Acad. Sci. Press.; 1974. Endemic nephropathy in immigrants living in foci of the disease in Lazarevac municipality; pp. 319–321. [Google Scholar]
- 31.Nichifor E., Balea M., Rusu G., Melencu M., Ghiordanescu N., Cristescu I., Dovlete C., Sonoc S. Studies on the familial character of endemic Balkan nephropathy. Possible role of the toxic hydric factor in the determination of “familial agglomerations” in endemic Balkan Nephropathy. Rev. Roum. Med., Med. Int. 1985;23:229–237. [PubMed] [Google Scholar]
- 32.Pavlovic M., Plestina R., Krogh P. Ochratoxin A contamination of foodstuffs in an area with Balkan (endemic) nephropathy. Acta Path. Microbiol. Scand. Sect. B. 1979;87:243–246. doi: 10.1111/j.1699-0463.1979.tb02433.x. [DOI] [PubMed] [Google Scholar]
- 33.Peric J. Proc. 3rd Symp. End. Nephr. Belgrade: Serbian Academy of Sciences and Arts; 1985. Hydrogeological field investigations and endemic nephropathy; pp. 105–122. [Google Scholar]
- 34.Peric J., Stefanovic D. Proc. 4th Symp. End. (Balkan) Nephr. Nis.: University Press.; 1979. Reliable correlations of some hydrogeological parameters with epidemiology in endemic and control villages affected by endemic nephropathy; pp. 61–68. [Google Scholar]
- 35.Petkova-Bocharova T., Castegnaro M. Ochratoxin A contamination of cereals in an area of high incidence of Balkan endemic nephropathy in Bulgaria. Food Addit. Contam. 1985;2:267–270. doi: 10.1080/02652038509373555. [DOI] [PubMed] [Google Scholar]
- 36.Petkova-Bocharova T., Chernozemsky I.N., Castegnaro M. Ochratoxin in human blood in relation to Balkan endemic nephropathy and urinary system tumours in Bulgaria. Food Addit. Contam. 1988;5:299–301. doi: 10.1080/02652038809373707. [DOI] [PubMed] [Google Scholar]
- 37.Radovanovic Z. Epidemiological evidence on Balkan nephropathy as a viral disease. Medical Hypotheses. 1987;22:171–175. doi: 10.1016/0306-9877(87)90140-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Radovanovic Z., Djordjevic G., Raicevic R., Velimirovic D., Velimirovic A., Jankovic S., Milkovic V. Endemic nephropathy in a defined locality -implications of a cross-sectional epidemiological study. Med. Invest. 1985;18:75–80. [Google Scholar]
- 39.Radovanovic Z., Markovic-Denic Lj., Marinkovic J. Proc. 6th Symp. End. (Balkan) Nephr. Nis.: University Press.; 1987. The role of water in the aetiology of endemic nephropathy - reevaluation of the evidence; pp. 15–25. [Google Scholar]
- 40.Radovanovic Z., Peric J. Hydrogeological characteristics of endemic nephropathy foci. Public Health, Lond. 1979;93:76–81. doi: 10.1016/s0033-3506(79)80093-1. [DOI] [PubMed] [Google Scholar]
- 41.Radovanovic Z., Stefanovic D. Different forms of mineral nitrogen in drinking water and the Balkan nephropathy. Arch. Environm. Contain. Toxicol. 1988;17:813–815. doi: 10.1007/BF01061986. [DOI] [PubMed] [Google Scholar]
- 42.Rusakiev M. Proc. 2nd Intern. Symp. End. Nephr. Nis.: University Press.; 1971. Investigation of sera of the endemic nephropathy patients for the presence of neutralizing antibodies against the West Nile virus; p. 32. [Google Scholar]
- 43.Stefanov Z. Proc. 2nd Symp. on End, Nephr. Nis.: University of Nis.; 1971. Experimental investigation on the etiological role of the drinking waters in the endemic nephropathy; pp. 18–20. [Google Scholar]
- 44.Strahinjic S., Levi-Jovovic E., Premovic P., Pavlovic N.M., Cukuranovic R., Stafanovic V. Proc. 6th Symp. End. (Balkan) Nephr. Nis.: University Press.; 1987. Investigation of the etiology and pathogenesis of endemic nephropathy; pp. 1–7. [Google Scholar]
- 45.Toncheva D., Dimitrov Ts., Tzoneva M. Cytogenetic studies in Balkan endemic nephropathy. Nephron. 1988;48:18–21. doi: 10.1159/000184862. [DOI] [PubMed] [Google Scholar]
- 46.Tucic N., Marinkovic D. The inheritance of liability to Balkan endemic nephropathy. Genetika. 1979;11:213–219. [Google Scholar]
- 49.Vorcugic A., Momcilovic V. Proc. 6th Symp. End. (Balkan) Nephropathy. Nis.: University Press; 1987. Some results of research on endemic nephropathy; pp. 187–197. [Google Scholar]
- 48.Wolstenholme G.E.W., Knight J., editors. The Balkan Nephropathy. Churcill, London: Ciba Foundation; 1967. [Google Scholar]
- 49.World Health Organisation The “Endemic Nephropathy” of South-Eastern Europe. Report on a Planning Conference. Bull. Wld. Hlth. Org. 1965;32:431–448. [PMC free article] [PubMed] [Google Scholar]
- 50.World Health Organisation (1974): WHO Meeting of Investigators on Endemic Nephropathy. Belgrade and Lazarevac. Nov. (1974): NCD/WP/74 (mimeo).
- 51.Yeulet S.E., Mantle P.G., Rudge M.S., Greig J.B. Nephrotoxicity of Penicillium aurantiogriseum, a possible factor in the aetiology of Balkan endemic nephropathy. Mycopathologia (Netherlands) 1988;102:21–30. doi: 10.1007/BF00436248. [DOI] [PubMed] [Google Scholar]