Abstract
Despite many hypotheses that have been challenged, the etiology of endemic nephropathy (EN) is still unknown. At present, the implications of aristolochic acid (AA) and mycotoxins (ochratoxin A—OTA and citrinin—CIT) are under debate. AA-theory is based on renal pathohistological similarities between Chinese herbs nephropathy (CHN) and EN, findings of AA-DNA adducts in EN and in patients with urinary tract tumors (UTT), as well as the domination of A:T®T:A transversions in the p53 mutational spectrum of UTT patients, which corresponds with findings of such mutations in AA-treated rats. However, exposure pathways of EN residents to AA are unclear. Experimental studies attempting to deduce whether nephrotoxins OTA and CIT appear at higher frequencies or levels (or both) in the food and blood or urine of EN residents support the mycotoxin theory. Also, some molecular studies revealed the presence of OTA-DNA adducts in the renal tissue of EN and UTT patients. In this review, data supporting or arguing against AA and mycotoxin theory are presented and discussed.
Highlights
Endemic nephropathy (EN) is a chronic kidney disease that affects the human population of some rural areas in Bosnia and Herzegovina, Bulgaria, Croatia, Romania, and Serbia
In the past 50 years, many studies exploring the possible role of various environmental factors in EN and urinary tract tumors (UTT) have been performed, and this includes research on heavy metals and minerals, bacteria (β-haemolytic streptococci, E. coli, and Leptospira spp.) and viruses, Pliocene lignites, aristolochic acid (AA), and mycotoxins [1,2,3,4,5]
Besides ochratoxin A (OTA), CIT and fumonisin B1 (FB1) could play an important role in development of EN, as well as other chronic kidney diseases of unknown etiology. This hypothesis is supported by the fact that these mycotoxins have synergistic, or at least additive interactions in vitro and in vivo: (1) the combination of OTA and CIT was found to have additive or synergistic effects on kidney impairment in chicks, mices, rats, guinea pigs, dogs, and swines, and synergistic cytotoxic effects on porcine and human kidney cell lines [44,45,46]; (2) the cytotoxic synergism of OTA and FB1 was reported for green monkey kidney Vero cells, rat brain glioma cells, and human intestinal Caco-2 cells [47]; (3) the combined treatment of porcine kidney PK15 cells with OTA and FB1 applied in low doses resulted in dominant pro-oxidative and genotoxic additive interactions and synergistic apoptotic effects [48,49,50]; and
Summary
Endemic nephropathy (EN) is a chronic kidney disease that affects the human population of some rural areas in Bosnia and Herzegovina, Bulgaria, Croatia, Romania, and Serbia. Between 1990 and 1992, a number of cases of interstitial nephropathy were reported in young women in Belgium who were undergoing a slimming regimen with Chinese herbs. The same group of investigators detected AA, instead of tetrandrine, in 10 out of 12 herbal powders in Belgium pharmacies sold between 1990 and 1992 under the name S. tetrandra These findings are not related to the reported renal failure in women involved within the weight-loss program. Nortier et al [9] found high level of AA-related DNA adducts in renal specimens obtained from the Chinese herbs nephropathy (CHN) patients (38/39) involved in weight-loss program, which supported chronic exposure to this phytotoxin.
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