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Review
. 2022 Aug;17(8):1220-1233.
doi: 10.2215/CJN.11290821. Epub 2022 Mar 10.

Drug-Induced Acute Kidney Injury

Mark A Perazella  1   2 , Mitchell H Rosner  3
Affiliations
Review

Drug-Induced Acute Kidney Injury

Mark A Perazella et al. Clin J Am Soc Nephrol. 2022 Aug.

Abstract

Medications are a common cause of AKI, especially for patients admitted to hospital wards and the intensive care unit. Although drug-related kidney injury occurs through different mechanisms, this review will focus on three specific types of tubulointerstitial injury. Direct acute tubular injury develops from several medications, which are toxic to various cellular functions. Their excretory pathways through the proximal tubules contribute further to AKI. Drug-induced AKI may also develop through induction of inflammation within the tubulointerstitium. Medications can elicit a T cell-mediated immune response that promotes the development of acute interstitial nephritis leading to AKI. Although less common, a third pathway to kidney injury results from the insolubility of drugs in the urine leading to their precipitation as crystals within distal tubular lumens, causing a crystalline-related AKI. Intratubular obstruction, direct tubular injury, and localized inflammation lead to AKI. Clinicians should be familiar with the pathogenesis and clinical-pathologic manifestations of these forms of kidney injury. Prevention and treatment of AKI relies on understanding the pathogenesis and judiciously using these agents in settings where AKI risk is high.

Keywords: Critical Care Nephrology and Acute Kidney Injury Series; acute interstitial nephritis; acute kidney injury; acute tubular injury; apoptosis; chronic kidney disease; crystalline nephropathy; drugs; inflammation; nephrotoxins.

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Figures

Figure 1.
Figure 1.
Mechanisms of drug-induced acute tubular injury. Filtered polycationic aminoglycosides (green) are attracted to the anionic phospholipid membranes where they interact with megalin-cubilin receptors on the apical surface. Aminoglycosides are endocytosed and enter the cell where they are translocated into lysosomes. Lysosomal injury with myeloid body formation and mitochondrial injury result in tubular cell apoptosis and/or necrosis. Cisplatin (red) is delivered to the basolateral membrane, transported into the cell via hOCT2, and excreted by various apical transporters including hMATE1 into the urinary space. Intracellular accumulation of cisplatin due to increased basolateral uptake or deficient efflux by hMATE1 transporters into the urine leads to tubular injury via production of a number of substances (TNF-α, TGF-β, and ROS), which promote mitochondrial toxicity. Tenofovir (blue) is delivered to the basolateral membrane, transported into the cell via hOAT1, and excreted by various apical transporters including MRP2 and -4 into the urinary space. When transport by MRP is inhibited or dysfunctional, intracellular accumulation of drug and tubular injury develop due to mitochondrial toxicity and reduced mitochondrial DNA synthesis. AG, aminoglycosides; Cis, cisplatin; hMATE1, human multidrug and toxin extrusion protein transporter; hOAT1, human organic anion transporter; hOCT2, human organic cation transporter–2; K+, potassium; MC, megalin-cubilin; MRP, multidrug resistance protein transporter; Na+, sodium; NaDC, sodium dicarboxylate transporter; Pgp, P-glycoprotein transporter; ROS, reactive oxygen species; TF, tenofovir.
Figure 2.
Figure 2.
Pathogenesis of drug-induced acute interstitial nephritis. Medications or their metabolites can incite an immune response through various processes. They can bind to TBM and act as haptens or prohaptens, Drugs can mimic an antigen that is normally present on TBM or interstitium, thereby inducing an immune response directed at this antigen. Drugs can also bind TBM or deposit within the interstitium, acting as a planted antigen. Dendritic and tubular cells present antigen to CD4+ naïve Th cells, stimulating the formation of various subsets of Th cells. These cells then produce various cytokines such as ILs and IFNs, which attract a number of cells (macrophages, eosinophils, CD8 T cells, and mast cells/basophils) to the tubulointerstitium. These cells can participate in the development of acute interstitial nephritis. TBM, tubular basement membrane; Th, T-helper. This figure was generously provided by Dr. Dennis Moledina, with permission.
Figure 3.
Figure 3.
Pathogenesis of drug-induced crystalline-related AKI. Drug crystals precipitating in the tubular lumen cause tubular obstruction (A) and induce tubular cell necroptosis by activating a number of pathways. Crystal uptake into lysosomes and phagolysomes is associated with release of ctp-B when the lysosomes are destabilized (B). ctp-B cleaves and degrades the negative regulator of necroptosis RIPK1, which triggers the formation of the RIPK3–MLKL necrosome complex, which causes tubular cell necroptosis (C). Necroptosis stimulates DAMPs, which induce TLR-dependent inflammation and cell necrosis (D). Dendritic cells phagocytose crystals present in the kidney interstitium (E) and activate NLRP3 inflammasome and IL-1β secretion by dendritic cells (F), which leads to IL-1 receptor–dependent inflammation in the kidney. Other cytokine and chemokine production produces further tubular injury and inflammation (G). Overall, these pathways promote an autoamplification loop of crystal-induced intrarenal inflammation. ctp, cathepsin-B; DAMPs, damage-associated molecular patterns; MLKL, mixed lineage kinase domain–like protein; NLRP3, NACHT-, LRR-, and PYD-domains–containing protein–3; RIPK1, receptor-interacting protein kinase–3; TLR, toll-like receptor.
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