Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid

Abstract

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through homebaked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.

Characterising Mutational Spectra of Carcinogens in the Tumour Suppressor Gene TP53 Using Human TP53 Knock-in (Hupki) Mouse Embryo Fibroblasts

“…Exposure to ultraviolet light induced a TP53 mutant frequency of 25%, with C→T transitions at dipyrimidine sites being the predominant mutation type in TP53 [39], which is in line with the formation of DNA photoproducts (i.e., cyclobutane pyrimidine dimers and (6-4) pyrimidine-pyrimidone photoproducts) [44]. The TP53 mutation pattern induced by the herbal drug aristolochic acid (AA) was dominated by A→T transversions which is in accordance with the formation of pre-mutagenic DNA adducts at adenine in DNA [45,46]. The TP53 mutant frequency in AA-exposed HUFs was 21-33% [12,39,40].…”

“…The same TP53 mutation pattern (i.e., A→T mutations) is found in urothelial tumours of patients suffering from aristolochic acid nephropathy (AAN) in Taiwan [47] ( Figure 17B). The A→T mutation type is otherwise rare in urothelial tumours [46] ( Figure 17C). As shown in Figure 17D the TP53 mutation pattern induced by AA in immortalised HUF cell lines closely mimics the pattern seen in AA-induced urothelial tumours in humans [12,39,40].…”

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

“…In the early 1990s, various women who were on a similar weight loss regimen, consisting of Chinese herbs, presented with a rapidly progressive form of CKD, known as Chinese herbal nephropathy (CHN) (Jadot et al, 2017). In addition, another form of nephropathy, more prominent in the Balkan region of Eastern Europe, hence known as Balkan endemic nephropathy (BEN), also exhibited similarities to CHN (Jelakovic et al, 2019). Further investigations led to the discovery of AA in the Chinese herbs, as the cause of CHN.…”

Predictive Markers for Malignant Urothelial Transformation in Balkan Endemic Nephropathy: A Case–Control Study

“…One of the most reliable diagnostic markers of BEN is β2-microglobulin, typical for tubular proteinuria [ 19 ]. Chronic renal failure, which occurs as the consequence of BEN, does not produce any specific symptoms, while symptoms of anemia and loss of appetite are generally present in most renal diseases [ 18 , 20 ].…”

“…The progression of BEN may follow a course towards two clinical entities: terminal renal failure, UC or combined [ 20 ]. The disorders associated with stimulated proliferation and/or deregulated programmed cell death are important in the process of carcinogenesis.…”