WORLD KIDNEY FORUM Balkan Nephropathy: Evolution of Our Knowledge Giorgos Bamias, MD,1 and John Boletis, MD2 Balkan endemic nephropathy (BEN), originally described in the late 1950s as a chronic tubulointerstitial kidney disease, is identified by its unique epidemio- logical features. The most remarkable characteristic of BEN is the focal topo- World Kidney Forum graphical nature that characterizes its occurrence at the global, national, and Advisory Board even household level. BEN affects only certain endemic rural foci along tributaries of the Danube River in the Balkan countries of Bosnia, Bulgaria, Croatia, Romania, and Serbia. The spatial distribution has remained astonish- Rashad S. Barsoum ingly unchanged with time because the disease affects the same endemic Cairo, Egypt clusters as 50 years ago. The natural course of the disease is characterized by universal development of end-stage renal disease and the frequent develop- Christopher R. Blagg ment of upper urinary tract tumors, posing a substantial disease burden to the Mercer Island, Washington afflicted areas. The greatest challenge in the study of BEN has been the John Boletis elucidation of its cause. The unique features of the disease, in particular its Athens, Greece endemic nature and the long incubation period required for the disease to develop, have led to the proposal that BEN represents a unique environmental Garabed Eknoyan disease. The quest for the responsible environmental factor has been long and Houston, Texas diverse, and although no definitive answer has been provided to date, converg- ing lines of evidence support the theory that long-term consumption of food John T. Harrington contaminated with aristolochic acid underlies the pathogenesis of BEN. The Boston, Massachusetts present review describes the evolution of our knowledge of BEN in relation to the development of the main theories for its pathogenesis. Am J Kidney Dis 52:606-616. © 2008 by the National Kidney Foundation, Inc. n 1956, the first description I of a novel form of intersti- disease at the regional hospital of Yugoslavia.2 This series of tial kidney disease appeared in from 1950 to 1954. He was the original publications was com- the non-English literature. The first to observe the remarkable pleted in 1961, as it became story had started a decade ear- clustering of the patients in vil- evident that a similar nephrop- lier, when local physicians noted lages, families, and even house- athy was also prevalent in dis- a high prevalence of kidney dis- holds. After presenting the condi- crete regions of Romania.3 ease in certain settlements in north- tion at local meetings in 1953 and As a consequence of these west Bulgaria in the district of proposing the term “endemic early reports, 2 scientific con- Vratza nephritis” in 1955, Tanchev Vratza. This prompted a thorough 1 ferences were organized to ad- investigation by Tanchev, who et al published the first de- dress the facts for the new dis- tailed clinical description of studied 664 patients with renal ease. The first was held by the the new entity in 1956. A year World Health Organization in later, a “family outbreak” of 1965, and the second, 2 years 1 renal disease was noticed in From the First Department of Pro- later, by the CIBA Founda- paedeutic Medicine, Laikon Hospital; the neighboring country of 4,5 and 2Department of Nephrology and (what was at the time) Yugosla- tion. As a result of these Transplant Center, Laiko Hospital, Ath- via; a mother and 2 daughters meetings, a novel nosological ens, Greece. had died of renal failure, and entity was recognized that was Received February 26, 2008. Ac- designated Balkan endemic ne- cepted in revised form May 8, 2008. the father and son also had Address correspondence to John Bo- severe renal damage. It was phropathy (BEN). The term letis, MD, 17 Agiou Thoma St, Athens, soon recognized that a disease epitomized the 2 predominant Greece. E-mail: [email protected] with almost identical clinical features of the new disease; © 2008 by the National Kidney Foun- first, it existed in the Balkans dation, Inc. and epidemiological pheno- 0272-6386/08/5203-0025$34.00/0 type to the Vratza nephritis exclusively, and, second, it oc- doi:10.1053/j.ajkd.2008.05.024 existed in confined rural areas curred in endemic clusters. 606 American Journal of Kidney Diseases, Vol 52, No 3 (September), 2008: pp 606-616 World Kidney Forum 607 In the following years, the clini- tal unless renal dialysis therapy in 142 settlements in the former cal and epidemiological character- is introduced. It therefore is Yugoslavia, 40 in Bulgaria, and istics of BEN were clarified.6-8 It evident that from the clinical 40 in southwest Romania, the represents a discrete form of stand point, the new entity only total area not exceeding 500 tubulointerstitial nephropathy added one more subcategory miles in length or 20,000 km2 with insidious presentation and to the long list of interstitial in surface (Fig 2). This geo- slow progression. Nonspecific renal diseases. BEN would graphic distribution is so stable symptoms and anemia typically have never achieved such sci- that 50 years after the original develop before significant renal entific attention and such nomi- description, no new endemic dysfunction.9,10 The latter ensues nated adjectives as “mysteri- areas have been reported and eventually and manifests as re- ous” and “enigmatic” if not for no endemic areas became free duced tubular transport, low-mo- its unique epidemiological from BEN. All affected re- lecular-weight proteinuria, and an characteristics. gions consist of villages or increase in serum urea nitrogen From the very beginning, it small towns built on the allu- level, but no high blood pressure was recognized that the most vial planes of tributaries of the or edema, findings usually en- remarkable feature of BEN is Danube River. In accord with countered in every form of ad- its focal nature.8,16-20 At the that observation, the disease af- vanced nephropathy.11,12 Histo- global level, the disease has fects only rural farming popu- logically, interstitial fibrosis and been described in Balkan coun- lations, but never inhabitants tubular atrophy are prominent fea- tries only: the aforementioned of big cities. The focal nature tures, as opposed to the absence Bulgaria and Romania, as well of BEN is so remarkably firm of significant inflammatory as Bosnia, Serbia, and Croatia, that afflicted villages are in changes (Fig 1).13-15 In the fi- countries formed after the divi- close proximity to unaffected nal stages, the kidneys are re- sion of the former Yugoslavia. ones, only 2 to 3 km apart. duced in size, sometimes On a national scale, BEN cases Finally, the focal nature is even weighing as little as 50 g and are not distributed evenly preserved at the local level. measuring just 2 to 3 cm.12,13 throughout each affected coun- That means that within an af- The outcome is universally fa- try. They are strictly confined fected village, one can find dis- eased households that exist next to disease-free ones. In a single household, only indi- viduals “living under the same roof and eating the same food” may be affected. However, BEN does not show a prefer- ence for specific ethnic or reli- gious groups. This was shown when Croatian aboriginals were compared with Ukrainian im- migrants in the area of Slavon- ski Brod in regard to several parameters of renal function. It was clearly shown that the sole factor determining the pres- ence or absence of pathologi- cal values was residency in an endemic versus a nonendemic area.21 Apart from its focal nature, Figure 1. Histological features of Balkan endemic nephropathy. The dense interstitial fibrosis is in contrast to the preservation of glomeruli. (Adapted from BEN is also characterized by a Nadasdy and Sedmak,15 with permission.) long incubation period. For an 608 Bamias and Boletis of the endemic villages were concerned, the reason was simple. The sudden misfortune that was laid upon their lives after the end of World War II could not have any other expla- nation but the interference of supernatural forces, divine or otherwise. It therefore was not unexpected that they tried to calm these forces with rituals and ceremonies and protect themselves by wearing amu- lets. However, for the health sci- entists, the unique characteris- tics of BEN offered different opportunities. This was a dis- Figure 2. Map shows the distribution of endemic foci of Balkan nephropa- ease with a distinct, homoge- thy. (Adapted with permission from Stefanovic and Cosyns.8) neous phenotype, affecting a small part of the world, con- individual to have the disease, increased risk of developing fined to certain recognized ar- he or she must live in the en- upper urinary tract tumors.23-26 eas, and with all the afflicted demic area for at least 15 to 20 This association was already people easily identifiable and years. This probably explains known in the 1960s, but be- therefore amenable to thor- why the disease has never been came more pronounced in later ough investigation and re- diagnosed in children. Accord- years when the life expectancy search. It therefore is not unex- ingly, a native who leaves the of patients with BEN increased pected that one of the first area before reaching the age of significantly as a result of the reports of BEN also announced 20 years is spared from devel- broad use of dialysis therapy. a definitive answer to its patho- oping BEN. Conversely, immi- The estimated incidence of tu- genesis, because Serbian inves- grants into an afflicted focus mors of urothelial origin has tigators considered it to be the become susceptible after liv- been 57 times greater in BEN result of lead poisoning of the ing there for 15 to 20 years.