Table 8.

Nephrotoxicity of OTA.

Year	Nephrotoxicity Testing	References
1972	Balkan endemic nephropathy (BEN) has been suggested to be the result of fungal poisoning. The role of OTA in mycotoxicosis—BEN in humans and porcine nephropathy.	[156]
1972	In view of the similarities between BEN and OTA induced porcine nephropathy, it has been suggested that OTA may be involved in the etiology of BEN.	[157]
1978	OTA is potentially nephrotoxic in all species tested with the exception of adult ruminants.	[158]
1987	Findings of higher OTA levels in the serum of patients suffering from BEN, which is a subtype of tubulointerstitial nephritis, led to hypotheses about the association between the nephrotoxicity of OTA and the BEN and also the incidence of renal system tumors in the population of these Balkan regions.	[159]
1991	Nephropathy is primarily related to the mobilization of intracellular calcium.	[160]
1992	In terms of human pathologies, OTA is suspected to be the main etiological agent responsible for BEN and associated urinary tract tumors (UTT) in humans.	[161]
1993	Experimental studies on the nephrotoxicity of OTA both in vitro and in vivo have shown that OTA disturbs the intracellular metabolic processes (with subsequent apoptosis of the renal cells), renal hemodynamics, and—significantly and perhaps preponderantly—the functions of the proximal tubules (even after subchronic exposition). OTA causes the decrease of glomerular filtration and tubular resorption and affects all parts of the nephron and kidneys in toto.	[162,163,164,165,166,167,168]
1993	A case of acute nephrotoxicity in humans.	[169,170]
1999	OTA induces apoptosis in cultured human proximal tubule cells.	[171]
2002–2005	The kidney is the main target of OTA toxicity in all animal species tested.	[14,172]
2002–2005	OTA has been also implicated in the etiology of BEN, a chronic degenerative kidney disease, in kidney tumors in humans in certain regions of the Balkan Peninsula, and in chronic interstitial nephropathy (CIN) in Tunisia and other North African countries.	[14,148,150]
2005	Exposure to low OTA doses is responsible for nephrotoxicity; at nanomolar concentrations, OTA leads to specific changes of function and phenotype in renal cells.	[173]
2007–2010	Very low OTA concentrations administered for a prolonged time (up to 14 days) influence the cellular fate (cellular hypertrophy) in human proximal tubule; furthermore, they act not only in the target organ, e.g., in the kidney, but also in as yet unsuspected cells, such as fibroblasts; the same damage will likely occur in chronic exposure.	[174,175]
2013	Nephrotoxicity is a consequence of acute, sub-acute, and also chronic exposure to OTA.	[9]
2014	OTA inhibits the nuclear factor, erythroid 2-like 2 (Nrf2) oxidative stress response pathway. Nrf2 overexpression confers a survival advantage and is often associated with cancer cell survival.	[176]
2015	Dietary exposure to OTA represents a serious health issue including, e.g., human endemic nephropathies.	[50]