FACTA UNIVERSITATIS Series: Medicine and Biology Vol.9, No 1, 2002, pp. 15 - 25 UC 616.61-004 BALKAN ENDEMIC NEPHROPATHY IN ROMANIA Gheorghe Gluhovschi1, Florin Margineanu2, Virginia Trandafirescu1, Adalbert Schiller1, Ligia Petrica1, Silvia Velciov1, Gheorghe Bozdog1, Cristina Gluhovschi1, Flaviu Bob1 1University of Medicine and Pharmacy "Victor Babes", Department of Nephrology, County Hospital, Timisoara, Romania, 2County Hospital, Drobeta Turnu Severin, Romania Summary. Balkan Endemic Nephropathy (BEN) is a disease with many similar epidemiological aspects in the countries in which it occurs. In spite of this, there are some particular aspects which have to be mentioned concerning this disease in Romania. BEN has a familial character; it is described in foci that consist of several families; sometimes families affected by the disease are found in the same village as families that are unaffected by BEN; also endemic villages may be encountered near unaffected villages. The clinico-biological picture of the disease is that of a tubulo-interstitial nephropathy. The etiology of BEN is unknown. Several factors are considered to be instrumental in the development of the disease: viral infections and mycotoxins. Key words: Balkan endemic nephropathy, epidemiology, etiology, kidney morphology, diagnosis, treatment Balkan endemic nephropathy (BEN) is a disease Gluhovschi, in collaboration with V. Stefanovic (Yugo- present in a limited geographical area in Romania, Bul- slavia) and T. Dimitrov (Bulgaria) (8). garia, Yugoslavia, Croatia and Bosnia. It is classified as a tubulointerstitial disease, with Epidemiology of the disease progressive evolution towards end-stage renal failure. In Romania it was first identified by Foarta and Ne- BEN is found predominantly in Oltenia, and also in goescu in 1957, and first published in 1961. some areas of Banat (regions in the SW of Romania). Interest in the study of this disease has existed in The best-known epidemiological studies are those of Romania since the first reports appeared regarding BEN Lazarescu (1) and Zaharia (9), who described 5 hotbeds: i.e.: epidemiological studies (1); the structure of the soil in Oltenia, where they are located around the town of as instrumental in the etiology of the disease (2,3); cy- Drobeta Turnu-Severin, Strehaia, Vanjul Mare, Baia de togenetic studies (4,5); pathological studies (6); studies Arama, and, in Banat, where there is one near Oravita. with regard to fertility impairment and evolution of The disease is present in the neighbouring villages, pregnancy in BEN patients (7). but not in towns, the BEN cases in the urban localities The most remarkable finding was the discovery by originating in the BEN villages (8). Georgescu et al. (6) of virus-like particles in the proxi- According to Zaharia (9) and Lazarescu (1), the vil- mal renal tubules in BEN patients. lages in which a large number of cases were found are: Studies on viral infections in BEN patients and in Erghevita, Bistrita, Poroina, Izvorul Anestilor, Sever- animals in the BEN area, the implication of mycotoxins, inesti, Simian, Cernet, Dodovita Veche, Fantana Dom- several immunology studies and studies regarding the neasca, Ghelmingioaia (villages grouped in the neigh- structure of the soil have also been carried out, but they bourhood of the town of Drobeta Turnu-Severin), Cor- have been either infrequent or are at an incipient stage. cova, Jirov, Stangaceaua, Tamna, Breznita, Motru, In recent years a hemodialysis centre has been set up Jeleni, Ruptura, Buicesti, Tantareni, Vagiulesti, Vanjul in the vicinity of the endemic area, at Drobeta Tr. Mare, Batosi, Broscari. Severin, which has provided renal replacement treat- In Banat the localities are: Secaseni, Jitin, Ticvanul ment for BEN patients in end-stage renal failure. Mare, Giurgiova. Lazarescu has mentioned cases in Some patients benefited from renal transplant un- villages in the area adjacent to Baia de Arama. dertaken in Romania or abroad. However, the number of An analysis performed by Margineanu in April, transplants is still small. 2000, on 51 patients included in the hemodialysis centre The findings regarding BEN have been communi- T. Severin, has revealed the following localities as those cated and published at various international congresses with the largest number of patients undergoing renal and in specialized journals. replacement therapies: Hinova - 4 hemodialysed pa- A monography was published in 1994, in a bilingual tients and one on peritoneal dialysis, Erghevita - 5 he- edition, entitled Endemic Balkan Nephropathy by Gh. modialysed patients, Bistrita - 5 hemodialysed patients, 16 G. Gluhovschi, F. Margineanu, V. Trandafirescu, et al. Husnicioara - 4 hemodialysed patients, Corcova - 4 he- firmed as yet. modialysed patients, Simian - 5 hemodialysed patients, Suggested factors in the etiology of the disease are: Valea Izvorului - 3 hemodialysed patients and 2 on • infectious factors, mainly viruses peritoneal dialysis, Vanjulet - 2 hemodialysed patients • toxic factors: mycotoxins, phenols, microelements, and 1 on peritoneal dialysis; Rogova - 4 hemodialysed silicium patients and 1 on peritoneal dialysis (Margineanu). • ionizing radiation It should be mentioned that of the 74 patients on • genetic factors hemodialysis at the Hemodialysis Centre in Drobeta • immune factors. Turnu-Severin, 46 patients have BEN (66%), and of the 16 patients on peritoneal dialysis, 5 patients have BEN. Infectious factors In the Department of Nephrology of the Drobeta Turnu-Severin County Hospital, (which consists of l2 There is a strong argument for viral etiology. The beds), 21 NEB patients were hospitalized over a period existence of hemorrhagic endemic nephropathy caused of 3 months, between January 1st 2000 and March 31st by the Hanta virus predominantly found in South-East 2000. Asia and in the Scandinavian countries, in relatively In the Department of Urology of the Drobeta Turnu- defined epidemiological areas has determined, by anal- Severin County Hospital, of the 33 patients with tumors ogy, the assumption that BEN is a chronic renal disease of the urinary tract, [20 males (60.6%) and 13 females of viral etiology. (39.3%)], 29 live or come from BEN areas (Margine- The investigations undertaken in order to isolate vi- anu- unpublished data). ruses from various biological samples taken from BEN The epidemiological features of the disease, ac- patients, have failed to isolate any virus which could be cording to our own observations and to those of other the cause of the disease; thus, no viral etiological agent authors are: could be attributed. However, the isolation of virus-like particles within • Predominance in adults aged 30-50 years the renal tubules has aroused interest in the study of • The disease has not been reported in children and viral etiology in this disease. adolescents These particles were reported in Romania by Geor- • Predominance in the female population gescu et al. (6) and Bruckner (10). • Village populations are affected. The cases found in However, the virus-like structures are not specific to towns are persons originating in BEN villages who BEN, being also reported in electron microscopy on moved to town or into small towns that resulted renal biopsies, in other renal diseases, too. from the development of BEN villages It is of great concern whether other microbial agents • The main occupation of the BEN patients is farming are involved in BEN. At present there is no evidence • BEN has a familial character, several members of a suggesting that infections with streptococcus or lepto- family being affected. These may belong to one gen- spira might be instrumental in causing this disease. eration or to 2 consecutive generations. Furthermore, other bacteria (brucella, salmonella, • Families with several BEN patients can be found shigella) and enterobacteriaceae, such as E. coli, Klebsi- beside families untouched by the disease: ella, could not be related directly to BEN etiology, due • There are unaffected localities beside affected lo- to the fact that these microorganisms are found in other calities geographical areas too. • The disease shows a cyclical evolution. There are Also, the investigations carried out by Lazarescu (1) periods with a significant number of cases and peri- aimed at revealing infection with Rickettsia (Burnetti, ods in which the number of cases diminishes. Connori, Maseri) as the cause of BEN have been incon- • Persons originating from the endemic zone and who clusive. have lived a long period in the endemic zone de- The possibility of BEN being a form of chronic velop the disease even if they move to a new locality pyelonephritis is very unlikely, as BEN inhabits a lim- after a variable period of time ited geographical area, while pyelonephritis is found • Persons who leave the endemic zone in their child- worldwide. hood or in adolescence will not develop the disease. • Persons coming from localities unaffected by BEN, Genetic factors may acquire the disease if they live several years in One characteristic of BEN is the presence of the disease a locality in the endemic area in several members of one family. This has raised the • There is a high incidence of tumors of the renal pel- possibility of the involvement of a hereditary factor. vis or of the ureter in BEN patients. Another hypothesis was that of the involvement of a toxic or viral factor. The incidence of the familial factor is variable. Etiology of BEN In Romania, Gh.Gluhovschi reported the presence of Although still