Pharmacology behind Common Drug Nephrotoxicities

Abstract

Patients are exposed to numerous prescribed and over-the-counter medications. Unfortunately, drugs remain a relatively common cause of acute and chronic kidney injury. A combination of factors including the innate nephrotoxicity of drugs, underlying patient characteristics that increase their risk for kidney injury, and the metabolism and pathway of excretion by the kidneys of the various agents administered enhance risk for drug-induced nephrotoxicity. This paper will review these clinically relevant aspects of drug-induced nephrotoxicity for the clinical nephrologist.

Keywords: Acute Kidney Injury; Drug Transporters; Humans; Nephrologists; Nonprescription Drugs; Pharmacology; Proximal Tubulopathy; Renal Elimination; Risk; acute renal failure; drug nephrotoxicity; kidney; metabolism.

Figure 1.

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.

Figure 2.

Patient factors that increase risk for drug-induced nephrotoxicity. Patients have risk factors from nonmodifiable characteristics such as age, sex, race, and the genetic makeup of immune response genes and drug metabolizing enzymes and transport pathways that enhance the nephrotoxicity of drugs. Comorbid conditions such as liver disease, heart disease, and CKD and acutely developed diseases such as intravascular volume depletion, metabolic perturbations, and AKI are also important risk factors for drug-induced nephrotoxicity.

Figure 3.

Kidney factors that enhance risk for drug-induced nephrotoxicity. High RBF increases drug delivery and exposure to the kidney. High metabolic rates of TALH tubular cells increase risk for drug nephrotoxicity. Kidney metabolism of drugs to toxic metabolites and ROS overwhelms local antioxidants and promotes tubular injury. Increased concentrations of potentially nephrotoxic drugs in the medulla and interstitium increase kidney injury. Apical uptake of certain drugs (aminoglycosides, hydroxyethyl starch) and basolateral transport of drugs through the organic anion transporter (tenofovir) and organic cation transporter (cisplatin) increase kidney toxicity. PCT, proximal convoluted tubule; RBF, renal blood flow; ROS, reactive oxygen species; TALH, thick ascending loop of Henle.

Figure 4.

Apical transport of drugs in the proximal tubule. (A) Aminoglycosides Apical membrane handling of substances, in this example aminoglycosides, by proximal tubular cells increases cellular uptake of this nephrotoxic drug. Polycationic aminoglycosides are attracted to the anionic phospholipid membranes where they interact with megalin-cubilin receptor on the apical surface. The aminoglycosides are endocytosed and enter the cell where they are translocated into lysosomes. Lysosomal injury and rupture along with mitochondrial injury result in tubular cell injury. (B) Hydroxyethyl starch. Apical membrane handling of hydroxyethyl starch by proximal tubular cells increases cellular uptake of this potentially nephrotoxic drug. Hydroxyethyl starch as well as sucrose (carrier for IVIg), dextran, and mannitol undergo pinocytosis and enter the cell where they are translocated into lysosomes. The lack of enzymes necessary to metabolize these substances allows accumulation within lysosomes, which causes cell swelling (occluding tubular lumens) and eventual lysosomal rupture resulting in tubular cell injury. AG, aminoglycosides; HES, hydroxyethyl starch; IVIg, intravenous immunoglobulin; K⁺, potassium; MC, megalin-cubilin; Na⁺, sodium; PL, anionic phospholipids.

Figure 5.

Basolateral transport of drugs. (A) Tenofovir. Basolateral handling of certain drugs, in this example tenofovir, by proximal tubular cells may lead to cellular injury. Tenofovir is delivered to the basolateral membrane, transported into the cell via the human organic anion transporter-1, and excreted by various apical transporters into the urinary space. In this example, transport by the multidrug-resistance protein transporters is inhibited or dysfunctional, causing intracellular accumulation of drug and nephrotoxicity via mitochondrial toxicity. (B) Cisplatin. Basolateral handling of certain drugs such as cisplatin by proximal tubular cells may lead to cellular injury. Cisplatin is delivered to the basolateral membrane, transported into the cell via the human organic cation transporter-2, and excreted by various apical transporters into the urinary space. Intracellular accumulation of cisplatin due to increased basolateral uptake or deficient efflux by the hMATE1 transporters into the urine leads nephrotoxicity via production of a number of substances (TNF-α, TGF-β, and ROS), which promote mitochondrial toxicity. Cis, cisplatin; hMATE1, human multidrug and toxin extrusion protein transporter; K⁺, potassium; MRP, multidrug resistance protein transporter; Na⁺, sodium; NaDC, sodium dicarboxylate transporter; OAT-1, organic anion transporter-1; OCT-1, organic cation transporter-1; Pgp, P-glycoprotein transporter; ROS, reactive oxygen species; TF, tenofovir; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α.