Drug factors associated with increased risk for nephrotoxicity. Drug factors associated with increased risk for nephrotoxicity. Medications cause kidney injury through various mechanisms. Increased exposure of the kidney on the basis of route, dose, and duration of drug exposure; drug-related immune effects (such as B-lactams, PPIs, NSAIDs, and immune checkpoint inhibitors); combined nephrotoxic drug exposure; and drug and metabolite insolubility in the urine (such as methotrexate, acyclovir, and sulfadiazine) lead to kidney injury. In addition, increased drug concentrations within tubular cells are due to transport effects (such as tenofovir and cisplatin), intracellular accumulation of certain drugs due to lack of metabolizing enzymes (such as sucrose and hydroxyethyl starch), innate direct cell toxicity (such as aminoglycosides, colistin, and amphotericin B), and intratubular cast formation from drugs interacting with uromodulin (vancomycin). ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; HES, hydroxyethyl starch; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton pump inhibitor; Tr, transporter. Mark A. Perazella CJASN 2018;13:1897-1908 ©2018 by American Society of Nephrology