Background: Organic anion transporters (OATs) are located on either the basolateral or the apical membrane of the proximal tubule cell and mediate the absorption and secretion of various drugs and endogenous metabolites. It has been shown that cellular damage in acute kidney injury (AKI) involves three forms of injury: sublethal damage resulting in loss of cell polarity, cell death through apoptosis and necrosis. We hypothesize that cellular mistargeting of OAT proteins in AKI will change the profile of OAT proteins in urine.
Methods: Thirty AKI patients were included in the study. AKI was defined by clinical course, daily urine output, response to fluid repletion, urinary sediment, fractional excretion of sodium (FeNa) and urine osmolality. Urinary OAT1, OAT3 and OAT4 protein abundance was measured from semiquantitative immunoblots of urine membrane fraction samples (exosome) collected from patients with AKI and from control subjects.
Results: Although all patients studied reached a similar severity of renal failure measured by serum creatinine, some of them recovered from AKI with supportive care only, while others required renal replacement therapy (RRT). OAT1 and OAT3, which are normally localized in the basolateral membrane of the proximal tubule cell, were detected at low levels in urine from control subjects and were increased significantly in all patients with AKI. OAT4 protein, which is normally localized in the luminal membrane of proximal tubule cells, was present in abundance in urine of control subjects. Interestingly, in patients with AKI who eventually recovered, urinary OAT4 was found to be significantly lower than in controls, while in patients who needed RRT, it was higher than in controls.
Conclusions: We have shown that OATs are mistargeted in AKI. The urinary OAT protein profile can help us to learn about the pathophysiology of the disease and might be a marker of AKI severity. AKI patients with early reversible proximal tubular damage will have high urine OAT1 and OAT3 and low OAT4, while patients with severe AKI will have high urine OAT1, OAT3 and OAT4.