Biology of drug-induced acute nephrotoxicity: focus on the tubulointerstitium

Abstract Drug-induced nephrotoxicity is a common and important cause of acute and chronic kidney injury. The kidneys receive ∼25% of the cardiac output exposing them to high drug concentrations. Additionally, the kidneys actively participate in drug metabolism and excretion, thereby further increasing their susceptibility to drug-related toxic effects. Any compartment of the renal parenchyma such as the glomerulus, vasculature, tubules and interstitium may be affected; however, the renal tubulointerstitium is the most frequent target. Several factors including patient’s comorbidities, genetic predisposition, degree of drug exposure and the drug’s biochemical structure and pharmacokinetics, affect one’s susceptibility to renal injury. Drug-induced acute tubulointerstitial injury has five distinct patterns and mechanisms of injury: 1. Direct acute tubular injury, 2. Acute tubulointerstitial nephritis, 3. Cast nephropathy, 4. Crystalline nephropathy, and 5. Osmotic nephropathy. Acute tubular injury is often dose-dependent, except in the case of acute tubulointerstitial nephritis, which is an idiosyncratic response to drug exposure and therefore independent of dose. Prevention and treatment of drug-induced tubulointerstitial injury relies primarily on understanding the pathogenesis, identifying injurious risk factors, close monitoring of kidney function and maintaining a high index of clinical suspicion when acute kidney injury (AKI), tubulopathies and chronic kidney disease (CKD) occur. This review will focus on the biology of drug-induced acute tubulointerstitial kidney injury, common causes, drug handling, mechanisms of injury, risk factors for nephrotoxicity, and key clinical characteristics.