ENDEMSKA NEFROPATIJA – BOLEST KOJA ZAHTEVA DALJA ISTRAŽIVANJA
Sažetak
Endemska nefropatija (EN) je hronična, tubulointersticijalna bolesti opisana pre 60 godina u ograničenim područjima Jugoistočne Evrope. Upkos brojnim istraživanjima ova bolesti i dalje privlači pažnju istraživača zbog većeg broja nerešnih pitanja. Nekima od tih pitanja posvećen je ovaj rad.
Obimna terenska istražaivanja sprovedena sedamdesetih godina prošlog veka u svim područjima ugroženim EN su pokazala različitu prevalenciju bolesti koja se kretala od 0,3% do 10%. Početkom ovog veka pojavila su se oprečna mišljenja o incidenciji bolesti, od pretpostavke da bolest iščezava do podataka da se incidencija ne menja značajno. Ove razlike su nastale kako zbog malog broja skrining studija urađenih tokom prethodnih 30 godina, tako i zbog velikih migracija stanovnika iz endemskih sela. Zato nema tačnih podataka o prevalenciji EN u endemskom područjima, a ni podataka o obolevanju emigranata iz endemskih naselja.
EN je porodična bolest koja se javlja samo u pojedinim žarištima pa se zato smatra da u njenom nastanku učestvuju genetski činioci i činioci spoljne sredine. Danas su aktuelne tri hipoteze o etiologiji EN. Jedna od najstarijih je ona o ohratoksinu A ali se najviše pažnje poklanja aristolohijskoj kiselini kao uzorku EN. Nije isključeno da su policiklični aromatični ugljovodonici i druga toksična organska jedinjenja poreklom iz lignita uzročnici EN.
Dosadašnja istraživanja nisu otkrila nijedan biomarker koji bi imao dovoljnu specifičnost i senzitivnost za otkrivanje i dijagnozu EN. Zato su definisani dijagnostički kriterijumi, koji predstavljaju kombinaciju epidemioloških, kliničkih i laboratorijskih parametara. Tokom proteklih decenija različite istraživačke grupe su koristile različite dijagnositčke kriterijume, što je otežavalo poređenje rezultata. Zbog toga je nedavno grupa ekpserata donela usaglašene preporuke za skrining, dijagnozu, klasifikaciju i lečenje EN. Međutim, kako ne postoji patognomoničan biomarker za EN, dijagnoza bolesti se postavlja na osnovu dokazivanja prisustva definisanih kriterijuma i isključivanja drugih bolesti bubrega. To ukazuje da traganje za specifičnim biomarkerom EN treba nastaviti.
Sve to govori da i posle 60 godina istraživanja EN postoje nerešena pitanja koja zahtevaju dalja istraživanja primenom savremenih metoda.
Reference
Tanchev I, Evstatijev P, Dorosiev D, Penčeva Y, Cvetkov E. Proučavania na nefritite v Vračanska okolija. Savr med. 1956; 7(9):14-25.
Danilović V, Djurišić M, Mokranjac M, Stojimirović B, Živojinović J, Stojaković P. Porodična oboljenja bubrega u selu Šopić izazvana olovom. Srp arh cel lek. 1957; 85:1115-1125.
Danilović V, Đurisić M, Mokranjac M, Stojimirović B, Živojinović J, Stojaković P. Nephrites chroniqes provoquees par l' intoxication an plomb par voie digestive (farine). La Presse Medicale 1957; 65(90):2039-2040.
Radovanović Z. Epidemiology and aetiology of endemic nephropathy. In: Radovanović Z, Sinđić M, Polenaković M, Djukanović Lj, Petronić V, editors. Endemic Nephropathy. Belgrade: Office for Textbooks and Teaching Aids; 2000. p. 22-152.
World Health Organization. Memorandum. The endemic nephropathy of South-Eastern Europe. Bull World Health Organ. 1965; 32:441-448.
Puchlev A. Endemic nephropathy in Bulgaria. In: Wolstenholme GEW, Knight J, editors. The Balkan Nephropathy. Ciba Foundation Study Group No. 30. London: Churchill; 1967. p. 28-39.
Radovanović Z. Topografska distribucija endemske nefropatije u SR Srbiji po naseljima. U: Zbornik radova. III simpozijum o endemskoj nefropatiji, Niš 1975. Beograd: Dokumenta Galenika; 1977. p. 30-39.
Gaon J, Dedić I, Aganović I, Mandić M, Telebak B. Epidemiološko ispitivanje endemske nefropatije na području SR Bosne i Hercegovine od 1957. do danas. In: Danilovic V, urednik. Zbornik radova II Simpozijuma o endemskoj nefropatiji, Beograd-Lazarevac 1977. Beograd: SANU; 1979. p. 9-25.
Velimirović D. Field investigation of the spread and frequensy of endemic nephropathy in the region of Kolubara. Acad Serbe Sciences Art Bull. 1980; 69:79-85.
Čeović S, Pleština R, Miletić-Medved M, Stavljenić A, Mitar J, Vukelić M. Epidemiological aspects of Balkan endemic nephropathy in tipical locus in Yugoslavia. In: Castagnero M, Plestina R, Dirheimer G, Chernozemsky IN, Bartsch H, editors. Mycotoxins, Endemic Nephropathy and Urinary Tract Tumors. Lyon: IARC Scientefic Publications; 1991. p. 5-10
Čukuranović R, Petrović B, Čukuranović Z, Stefanović V. Balkan endemic nephropathy: a decreasing incidence of the disease. Pathol Biol (Paris). 2000; 48:558-561.
Dimitrov PS, Simeonov VA, Ganev VS, Karmaus WJ. Is the incidence of Balkan endemic nephropathy decreasing? Pathol Biol (Paris). 2002; 50: 38–41.
Djukanović L, Stefanović V, Basta-Jovanović G, Bukvić D, Glogova S, Dimitrijević J, i sar. Istraživanja Balkanske endemske nefropatije u Srbiji: kako dalje? Srp arh celok lek. 2010; 138(3 4):256-261.
Bukvic D, Jankovic S, Maric I, Stosovic M, Arsenovic A, Djukanovic L. Today Balkan endemic nephropathy is a disease of the elderly with a good prognosis. Clin Nephrol. 2009; 72(2):105-113.
Bukvić D, Janković S, Arsenović A, Djukanović L. Balkan endemic nephropathy is still present in the Kolubara region, Ser bia. Ren Fail. 2005; 27: 565-569.
Bukvić D, Marić I, Arsenović A, Janković S, Djukanović L. Prevalence of Balkan endemic nephropathy has not changed since 1971 in the Kolubara region in Serbia. Kidney Blood Press Res. 2007; 30:117-123.
Radovanović Z. Epidemiološka istraživanja endemske nefropatije – dokle se stiglo i kuda dalje? U: Djukanović Lj, Ristić S, urednici. Savremena istraživanja endemske nefropatije. Foča: Medicinski fakultet Univerziteta Istočno Sarajevo; 2009. str. 117-130.
Janković S, Bukvić D, Marinković J, Janković J, Marić I, Djukanović Lj. Time trends in Balkan endemic nephropathy incidence in the most affected region in Serbia, 1977–2009: the disease has not yet disappeared. Nephrol Dial Transplant. 2011: 26:2171-2176.
Janković S, Bukvić D, Marinković J, Janković J, Marić I, Djukanović L. Trends in incidence and prevalence of Balkan endemic nephropathy in the three most affected villages in Serbia over a 36-year period. Ren Fail. 2013; 35(4):509-13.
Petković S, Mutavdžić M, Petronić V, Marković V. Les tumeurs di bassinet et de l' uretére. Recherches cliniques et étiologiques. J Urol Néphrol. 1971; 6:429-439.
Petronić V, Bukurov N, Djokić M, Milenković DZ, Vuksanović AM, Avramović AD, et al. Balkan endemic nephropthy (BEN) and papillary transitional cell tumors of the renal pelvis and ureters (UTT): A folow-up study. Kidney Int. 1991; 40(Suppl 34):S77-79.
Petronić V. Tumors of the upper urothelium and endemic nephropathy. In: Radovanović Z, Sindjić M, Polenaković M, Djukanović Lj, Petronić V, editors. Endemic nephropathy. Office for Textbooks and Teaching Aids, Beograd, 2000.
Markovic N, Ignjatovic I, Cukuranovic R, Petrovic B, Kocic B, Stefanovic V. Decreasing incidence of urothelial cancer in a Balkan endemic nephropathy region in Serbia. A surgery based study from 1969 to 1998. Pathol Biol (Paris). 2005; 53:26-29.
Bukvić D, Janković S, Marković-Denić Lj. Neke deskriptivno epidemiološke odlike osoba obolelih od malignih tumora gornjeg urotelijuma u endemskom regionu Lazarevca. Srp arh cel lek. 1999; 127:371-375.
Bukvić D, Velimirović D, Marić I, Popović G, Trbojević S. Tumori urinarnog sistema kod bolesnika sa endemskom nefropatijom na hroničnoj hemodijalizi. Srp arh cel lek. 1995; 123:15-21.
Ivic M. Etiologija endemske nefropatije. Lijec Vjesn. 1969; 91:1278-1281.
Vanherweghem JL, Depierreux M, Tielemans C, Abramowicz D, Depierreux M, Vanhaelen-Fastre R, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 1993; 341:387-391.
Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL. Identification of aristolochic acid in Chinese herbs. Lancet 1994; 343:174.
Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int. 2008; 74(2):158-169.
De Broe ME. Chinese herbs nephropathy and Balkan endemic nephropathy: toward a single entity, aristolochic acid nephropathy. Kidney Int. 2012; 81(6):513-515.
Grollman AP, Shiburani S, Moriya M, Miller F, Wu L, MoU U, et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc Nad Acad Sci USA. 2007; 104:12129-34.
Jelakovic B, Karanovic S, Vukovic-Lela I, Miller F, Fdwards KL, Nikolic J, et al. Aristolactam-DNA adducts are a biomarker of environmenral exposure to aristolochic acid. Kidney Int. 2012; 81:559-67.
Krogh P, Gyrd-Hansen N, Hald B, Larsen S, Nielsen JP, Smith M, et al. Renal enzyme activities in experimental ochratoxin A-induced porcine nephropathy: diagnostic potential of phosphoenolpyruvate carboxykinase and gamma-glutamyl transpeptidase activity. J Toxicol Environ Health. 1988; 23:1-14.
Krogh P, Hald B, Pleština R, Čeović S. Balkan (endemic) nephropathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs. Acta Pathol Microbiol Scand. 1977; 85:238-240.
Maaroufi K, Achour A, Betbeder AM, Hammami M, Ellouz F, Creppy EE, et al. Foodstuffs and human blood contamination by the mycotoxin ochratoxin A: correlation with chronic interstitial nephropathy in Tunisia. Arch Toxicol. 1995; 69:552-558.
Domijan AM, Peraica M, Fuchs R, Lučić A, Radić B, Balija M, et al. Ochratoxin A in blood of healthy population in Zagreb. Arh Hig Rada Toksikol. 1999; 50: 263-271.
Kuiper-Goodman T. Risk assessment of ochratoxin A residues in food. IARC Sci Publ. 1991; 115:307-320.
Puntarić D, Bosnir J, Smit Z, Skes I, Baklaić Z. Ochratoxin A in corn and wheat: geographical association with endemic nephropathy. Croat Med J. 2001; 42(2):175-80.
Pfohl-Leszkowicz A, Tozlovanu M, Manderville R, Peraica M, Castegnaro M, Stefanovic V. New molecular and field evidences for the implication of mycotoxins but not aristolochic acid in human nephropathy and urinary tract tumor. Mol Nutr Food Res. 2007; 51:1131-1146.
Pfohl-Leszkowicz A, Grosse Y, Castegnaro M, Nicolov IG, Chernozemsky IN, Bartsch H, et al. Ochratoxin A-related DNA adducts in urinary tract tumours of Bulgarian subjects. IARC Sci Publ. 1993; 124:141-148.
Yordanova P, Wilfried K, Tsolova S, Dimitrov P. Ochratoxin A and β2-microglobulin in BEN patients and controls. Toxins (Basel). 2010;2(4):780-792.
Feder GL, Radovanović Z, Finkelman RB. Relationship between weathered coal deposits and the etiology of Balkan endemic nephropathy. Kidney Int. 1991; 40 (Suppl. 34):S9-S11.
Maharaj SV, Orem WH, Tatu CA, Lerch HE 3rd, Szilagyi DN. Organic compounds in water extracts of coal: links to Balkan endemic nephropathy. Environ Geochem Health. 2014; 36:1-17.
Orem WH, Feder GL, Finkelman RB. A possible link between Balkan endemic nephropathy and the leaching of toxic organic compounds from Pliocene lignite by groundwater: preliminary investigation. Int J Coal Geol 1999; 40:237-252.
Voice TC, McElmurry SP, Long DT, Dimitrov P, Ganev VS, Peptropoulos EA Evaluation of the hypothesis that Balkan endemic nephropathy is caused by drinking water exposure to contaminants leaching from Pliocene coal deposits. J Exp Sci Environ Epidemiol. 2006; 16:515-524.
Atanasova SY, von Ahsen N, Toncheva DI, Dimitrov TG, Oellerich M, Armstrong VW. Genetic polymorphisms of cytochrome P450 among patients with Balkan endemic nephropathy (BEN). Clin Biochem. 2005; 38(3):223-228.
Pećin I, Čvorišćec D, Miletić-Medved M, Dika Z, Cvitković A, Vitale K, et al. Angiotensin-converting enzyme gene polymorphism and N-Acetyl-β-D-glucosaminidase excretion in endemic nephropathy. Nephron Clin Pract. 2011; 119(2):c105-112.
Reljic Z, Zlatovic M, Savic-Radojevic A, Pekmezovic T, Djukanovic L, Matic M, et al. Is increased susceptibility to Balkan endemic nephropathy in carriers of common GSTA1 (*A/*B) polymorphism linked with the catalytic role of GSTA1 in ochratoxin a biotransformation? Serbian case control study and in silico analysis. Toxins (Basel). 2014; 6(8):2348-2362.
Stiborová M, Arlt VM, Schmeiser HH. Balkan endemic nephropathy: an update on its aetiology. Arch Toxicol. 2016 Aug 19. PMID: 2738407; doi: 10.1007/s00204-016-1819-3
Danilović V. Endemic nephropathy in Yugoslavia. In: Strahinjic S, Stefanovic V, editors. Endemic (Balkan) Nephropathy, Proceedings 4th Symp., Niš, 1979. Niš: Institute of Nephrology and Haemodialysis; 1981. p. 1-5.
Puchlev A, Dimitrov TS, Dinev I, Doichinov D. Clinical investigations in patients with endemic nephropathy. In: Strahinjic S, Stefanovic V, editors. Endemic (Balkan) Nephropathy, Proc. 4th Symp., Nis 1979. Nis: Institute of Nephrology and Haemodialysis; 1981. p. 7-10.
Stefanović V. Diagnostic criteria for Balkan endemic nephropathy. In: Strahinjić S, Stefanović V, editors. Proceedings of the 5th Symposium on Endemic (Balkan) Nephropathy, Niš 1983. Niš: University Press; 1983. p. 351-363.
Čvorišćec D, Radonić M, Čeović S, Aleraj B. Characteristics of proteinuria in ednemic nephropathy. J Clin Chem Clin Biochem. 1983; 21:569-571.
Jelaković B, Nikolić J, Radovanović Z, Nortier J, Cosyns J P, Grollman A P, et al. Consensus statement on screening, diagnosis, classification and treatment of endemic (Balkan) nephropathy. Nephrol Dial Transplant. 2013; 29(11):2020-2027.
Hall PW, Vasiljevic M. Beta 2-microglobulin exretion as an index of renal tubular disorders with special reference to endemic Balkan nephropathy. J. Lab Clin Med (St. Luis). 1973; 81:897-904.
Djukanović Lj. Laboratory studies. In: Radovanović Z, Sinđić M, Polenaković M, Djukanović Lj, Petronić V, editors. Endemic Nephropathy. Belgrade: Office for Textbooks and Teaching Aids, 2000. p. 317-349.
Djukanović L, Marić I, Marinković J, Ignjatović S, Bukvić D. Evaluation of criteria for the diagnosis of Balkan endemic nephropathy. Ren Fail. 2007; 29(5):607-614.
Djukanović L, Marinković J, Marić I, Ležaić V, Dajak M, Petronić D, et al. Contribution to the definition of diagnostic criteria for Balkan endemic nephropathy. Nephrol Dial Transplant. 2008; 23(12):3932-3938.
Stefanović V, Jelaković B, Čukuranović R, Bukvic D, Nikolic J, Lukic L, et al. Diagnostic criteria for Balkan endemic nephropathy: proposal by an international panel. Ren Fail. 2007; 29:867-880.
KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Chapter 1: Definition and classification of CKD. Kidney Int Suppl. 2013: 3;19-62.
