Balkan endemic nephropathy-current status and future perspectives

Abstract

Balkan endemic nephropathy (BEN), originally described in 1956, is a unique familial, chronic renal disease encountered with a high-prevalence rate in Serbia, Bulgaria, Romania, Croatia and Bosnia and Herzegovina. The most prominent features of the disease are its endemic nature, long-incubation period, familial clustering of the disease and an unusually high incidence of associated upper urothelial cancer (UUC). There are no clear-cut data on BEN incidence and prevalence, since the studies carried out in different endemic areas yielded contradictory information. In spite of intermittent variations, the incidence of new cases has remained stable over time. It has been estimated that almost 100 000 people are at risk of BEN, whereas 25 000 have the disease. The clinical signs and symptoms of BEN are non-specific and often remain unrecognized for years. There are no pathognomonic diagnostic features of BEN, but the set of epidemiological, clinical and biochemical data along with the pattern of pathologic injury in the absence of any other renal diseases are highly suggestive of this entity. Although the aetiology has been extensively studied, fostering the publication of various hypotheses, only one of them has provided conclusive evidence related to the aetiology of BEN. Studies conducted over the past decade have provided particularly strong arguments that BEN and UUC are caused by chronic poisoning with aristolochic acids (AAs). In light of these later studies, one can raise the question whether AAs could be responsible for previously and currently widespread unrecognized global renal disease and UUC.

Keywords: Balkan endemic nephropathy; aetiology; aristolochic acid; hypothesis; urothelial cancer.

Fig. 1.

Geographical distribution of endemic foci and pliocene lignite coal deposits.

Fig. 2.

(A) Advanced glomerular sclerosis (initial obsolescence), with interstitial sclerosis and tubular atrophy (PAS, ×250); (B) Focal tubular atrophy with prominent interstitial sclerosis and clearly delineated mononuclear infiltrate (PAS, ×250) [R. Čukuranović. Genetic and morphophysiologic study of BEN. Doctoral Thesis. Medical Faculty, University of Niš, 1–169, 1992 (in Serbian)].

Fig. 3.

Post harvests second generation Aristolochia Clematitis growing in the wheat field (A), with ripe seeds in the soil (B) and wheat grain from that field (C) (hyperendemic village Petka, Serbia, 2011).

Fig. 4.

TP53 mutational spectra in urothelial carcinomas. (A) TP53 mutations in DNA obtained from UUC in endemic regions of Bosnia, Croatia and Serbia (62 mutations); (B) TP53 mutations in DNA obtained from UUC in Taiwan (113 mutations); (C) TP53 mutations in urothelial carcinomas of the renal pelvis and ureter, worldwide (73 mutations); (D) TP53 mutations in urothelial carcinomas of the renal pelvis, ureter, bladder and nonspecified urinary organs, worldwide (696 mutations)[61].