Renal drug transporters and nephrotoxicity

Among drug-induced renal failure, direct renal tubular toxicity, typically described as toxic acute tubular necrosis, is often associated with increased cellular uptake of nephrotoxic compounds. Drug transporters in tubular cells are the first fundamental stage in the development of the nephrotoxic process. Several examples can be given of organic substances that are nephrotoxic only after being transported into the cells. Recent advances in molecular cloning have identified several families of multispecific drug transporters: organic anion and cation transporter (OAT/OCT) family, organic anion-transporting polypeptide (OATP) family, type I sodium-phosphate transporters (NPTs) and ATP-dependent organic ion transporters such as MDR1/ P-glycoprotein ABCB and the multidrug resistance-associated protein (MRP) family ABCC. In addition, peptide transporter (PEPT) family and recently identified multidrug and toxin extrusion (MATE) transporters have been shown to either transport or interact with several drugs. Nephrotoxicity appears to be proportional to the final drug concentration, though the intrinsic characteristics of the drug, particularly its "reactivity", meaning its ability to react irreversibly with the intracellular targets, are also important. Knowledge of these concepts is important for the prevention of iatrogenic kidney injury, particularly in patients with underlying disease receiving concomitant treatment with several potentially nephrotoxic agents.