Balkan endemic nephropathy
- Marc E De Broe, MD, PhD
Marc E De Broe, MD, PhD
- Emeritus Professor of Medicine
- University of Antwerp, Belgium
Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease associated with a high frequency of urothelial atypia, occasionally culminating in tumors of the renal pelvis and urethra.
Affected patients most commonly reside in southeastern Europe, including the areas traditionally considered to comprise the Balkans: Serbia, Bosnia and Herzegovina, Croatia, Romania, and Bulgaria. More specifically, BEN is most likely to occur among those living along the confluence of the Danube River, a region in which the plains and low hills generally have high humidity and rainfall. The most likely cause of BEN is exposure to aristolochic acid (AA). In contrast to the classic presentation of AA nephropathy, which is characterized by a rapid decline in renal function (six months to two years), BEN is slowly progressive (10 to 20 years), however, likely due to low-level exposure.
This topic reviews BEN. The classic presentation of AA nephropathy is discussed elsewhere. (See "Nephropathy induced by aristolochic acid (AA) containing herbs".)
The estimated prevalence of BEN in endemic areas ranges between 0.5 to 4.4 percent . It has been suggested that the prevalence would be as high as 20 percent if aggressive screening were to be performed in at-risk populations; a striking observation is that nearly all affected patients were farmers. In some regions in Bosnia, approximately 10 percent of the patients on dialysis have BEN as the cause of end-stage renal disease (ESRD) .
Subsequent reports, however, suggest that the incidence of BEN is decreasing . Since the early 1990s, the few new cases in one region in Serbia were only seen in previously affected families [4,5].
- Ceović S, Hrabar A, Sarić M. Epidemiology of Balkan endemic nephropathy. Food Chem Toxicol 1992; 30:183.
- Djukanović L, Radović M, Baković J, et al. Epidemiology of end-stage renal disease and current status of hemodialysis in Yugoslavia. Int J Artif Organs 2002; 25:852.
- Dimitrov PS, Simeonov VA, Ganev VS, Karmaus WJ. Is the incidence of Balkan endemic nephropathy decreasing? Pathol Biol (Paris) 2002; 50:38.
- Bukvić D, Janković S, Arsenović A, Djukanović L. Balkan endemic nephropathy is still present in the Kolubara region, Serbia. Ren Fail 2005; 27:565.
- Arsenović A, Bukvić D, Trbojević S, et al. Detection of renal dysfunctions in family members of patients with Balkan endemic nephropathy. Am J Nephrol 2005; 25:50.
- Stefanovic V, Toncheva D, Atanasova S, Polenakovic M. Etiology of Balkan endemic nephropathy and associated urothelial cancer. Am J Nephrol 2006; 26:1.
- Bamias G, Boletis J. Balkan nephropathy: evolution of our knowledge. Am J Kidney Dis 2008; 52:606.
- Gökmen MR, Cosyns JP, Arlt VM, et al. The epidemiology, diagnosis, and management of aristolochic acid nephropathy: a narrative review. Ann Intern Med 2013; 158:469.
- Ivic M. The problem of etiology of endemic nephropathy. Acta Fac Med Naiss 1970; 1:29.
- Cosyns JP, Jadoul M, Squifflet JP, et al. Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994; 45:1680.
- De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int 2012; 81:513.
- Grollman AP, Shibutani S, Moriya M, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Natl Acad Sci U S A 2007; 104:12129.
- Arlt VM, Schmeiser HH, Pfeifer GP. Sequence-specific detection of aristolochic acid-DNA adducts in the human p53 gene by terminal transferase-dependent PCR. Carcinogenesis 2001; 22:133.
- Jelaković B, Karanović S, Vuković-Lela I, et al. Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int 2012; 81:559.
- Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int 2008; 74:158.
- Radovanovic Z. Aetiology of Balkan nephropathy: a reappraisal after 30 years. Eur J Epidemiol 1989; 5:372.
- Riquelme C, Escors D, Ortego J, et al. Nature of the virus associated with endemic Balkan nephropathy. Emerg Infect Dis 2002; 8:869.
- Puntarić D, Bosnir J, Smit Z, et al. Ochratoxin A in corn and wheat: geographical association with endemic nephropathy. Croat Med J 2001; 42:175.
- Hassen W, Abid S, Achour A, et al. Ochratoxin A and beta2-microglobulinuria in healthy individuals and in chronic interstitial nephropathy patients in the centre of Tunisia: a hot spot of Ochratoxin A exposure. Toxicology 2004; 199:185.
- Kamp HG, Eisenbrand G, Schlatter J, et al. Ochratoxin A: induction of (oxidative) DNA damage, cytotoxicity and apoptosis in mammalian cell lines and primary cells. Toxicology 2005; 206:413.
- Castegnaro M, Canadas D, Vrabcheva T, et al. Balkan endemic nephropathy: role of ochratoxins A through biomarkers. Mol Nutr Food Res 2006; 50:519.
- Vrabcheva T, Petkova-Bocharova T, Grosso F, et al. Analysis of ochratoxin A in foods consumed by inhabitants from an area with balkan endemic nephropathy: a 1 month follow-up study. J Agric Food Chem 2004; 52:2404.
- Voice TC, McElmurry SP, Long DT, et al. Evaluation of the hypothesis that Balkan endemic nephropathy is caused by drinking water exposure to contaminants leaching from Pliocene coal deposits. J Expo Sci Environ Epidemiol 2006; 16:515.
- Li X, Wang H. Aristolochic acid nephropathy: what we know and what we have to do. Nephrology (Carlton) 2004; 9:109.
- Toncheva D, Dimitrov T, Tzoneva M. Cytogenetic studies in Balkan endemic nephropathy. Nephron 1988; 48:18.
- Krasteva ME, Georgieva EI. Germline p53 single-base changes associated with Balkan endemic nephropathy. Biochem Biophys Res Commun 2006; 342:562.
- Dimitrov P, Tsolova S, Georgieva R, et al. Clinical markers in adult offspring of families with and without Balkan Endemic Nephropathy. Kidney Int 2006; 69:723.
- Batuman V. Fifty years of Balkan endemic nephropathy: daunting questions, elusive answers. Kidney Int 2006; 69:644.
- Stefanović V, Polenaković MH. Balkan nephropathy. Kidney disease beyond the Balkans? Am J Nephrol 1991; 11:1.
- Toncheva D, Galabov AS, Laich A, et al. Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN). Kidney Int 2003; 64:1817.
- Cukuranovic R, Savic V, Stefanovic N, Stefanovic V. Progression of kidney damage in Balkan endemic nephropathy: a 15-year follow-up of patients with kidney biopsy examination. Ren Fail 2005; 27:701.
- Polenakovic MH, Stefanovic V. Balkan nephropathy. In: Oxford Textbook of Clinical Nephrology, 2nd ed., Davison AM, Cameron JS, Grünfeld JP, et al (Eds), Oxford Medical Publications, 1998. p.1203.
- Djukanovic L, Bukvic D, Maric I. Creatinine clearance and kidney size in Balkan endemic nephropathy patients. Clin Nephrol 2004; 61:384.
- Petronić VJ, Bukurov NS, Djokić MR, et al. Balkan endemic nephropathy and papillary transitional cell tumors of the renal pelvis and ureters. Kidney Int Suppl 1991; 34:S77.
- Sattler TA, Dimitrov T, Hall PW. Relation between endemic (Balkan) nephropathy and urinary-tract tumours. Lancet 1977; 1:278.
- Cukuranović R, Ignjatović M, Stefanović V. Urinary tract tumors and Balkan nephropathy in the South Morava River basin. Kidney Int Suppl 1991; 34:S80.
- Stewart JH, Buccianti G, Agodoa L, et al. Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand. J Am Soc Nephrol 2003; 14:197.
- Djukanovic L, Radovanovic Z. Balkan endemic nephropathy. In: Clinical Nephrotoxins - Renal Injury from Drugs and Chemicals, De Broe ME, Porter GA, Bennett WM, Verpooten GA (Eds), Kluwer Academic Publications, Dordrecht 2003. p.587.