RENAL TOXICODYNAMICS OF OCHRATOXIN-A - A PATHOPHYSIOLOGICAL APPROACH

Ochratoxin A (OTA) is a secondary fungal metabolite that has been dete cted in a variety of animal chows, human food and in up to 80% of huma n blood samples of several Western countries. Its main target is the k idney. OTA is the causing agent of Danish porcine nephropathy and incr eases the incidence of renal carcinomas and adenomas in rats. Pathophy siological studies revealed that OTA acts on different sites along the nephron. Acute OTA exposure leads to an impairment of postproximal ne phron function, predominantly of the collecting duct, resulting in alt ered electrolyte and titratable acid excretion. The underlying mechani sm is most probably a blockade of anion conductance in the plasma memb rane at nanomolar concentrations of OTA with subsequent disturbance of cellular acid-base homeostasis as shown in cultured kidney cells. Dis turbance of cellular pH homeostasis is probably also involved in OTA-i nduced transformation of cultured kidney cells. Chronic OTA exposure l eads to an additional reduction in the urine concentrating ability. Re nal hemodynamics and the secretory function of the proximal tubule are affected by OTA after prolonged but not by acute exposure. OTA increa ses resistance in the vas efferens with a subsequent decrease in renal blood flow and glomerular filtration rate. Proximal tubular cells res pond to OTA with a dramatic reduction in the secretory capacity for or ganic anions. The resorptive capacity for small molecules like amino a cids is affected only to a minor extent, whereas endocytic uptake of a lbumin is clearly reduced. Furthermore, OTA has a mitogenic potential on rat proximal tubular cells in primary culture if applied in nanomol ar concentrations but inhibits cell growth at micromolar concentration s. According to the above-described effects OTA exerts a complex actio n on renal function depending on the dose and time of exposure. The hi gh incidence of OTA in human food and blood samples taken together wit h its diverse effects on renal function should attract further attenti on to this mycotoxin as a possible candidate for renal malfunction of unknown origin in humans.