Renal toxicodynamics of ochratoxin A: a pathophysiological approach.

Abstract

Ochratoxin A (OTA) is a secondary fungal metabolite that has been detected in a variety of animal chows, human food and in up to 80% of human blood samples of several Western countries. Its main target is the kidney. OTA is the causing agent of Danish porcine nephropathy and increases the incidence of renal carcinomas and adenomas in rats. Pathophysiological studies revealed that OTA acts on different sites along the nephron. Acute OTA exposure leads to an impairment of postproximal nephron function, predominantly of the collecting duct, resulting in altered electrolyte and titratable acid excretion. The underlying mechanism is most probably a blockade of anion conductance in the plasma membrane at nanomolar concentrations of OTA with subsequent disturbance of cellular acid-base homeostasis as shown in cultured kidney cells. Disturbance of cellular pH homeostasis is probably also involved in OTA-induced transformation of cultured kidney cells. Chronic OTA exposure leads to an additional reduction in the urine concentrating ability. Renal hemodynamics and the secretory function of the proximal tubule are affected by OTA after prolonged but not by acute exposure. OTA increases resistance in the vas efferens with a subsequent decrease in renal blood flow and glomerular filtration rate. Proximal tubular cells respond to OTA with a dramatic reduction in the secretory capacity for organic anions. The resorptive capacity for small molecules like amino acids is affected only to a minor extent, whereas endocytic uptake of albumin is clearly reduced. Furthermore, OTA has a mitogenic potential on rat proximal tubular cells in primary culture if applied in nanomolar concentrations but inhibits cell growth at micromolar concentrations. According to the above-described effects OTA exerts a complex action on renal function depending on the dose and time of exposure. The high incidence of OTA in human food and blood samples taken together with its diverse effects on renal function should attract further attention to this mycotoxin as a possible candidate for renal malfunction of unknown origin in humans.