Prescribed and over-the-counter medications are vital for health, however, acute kidney injury (AKI) is one of many potential adverse complications [1,2,3▪,4–6]. Although all nephron segments can be injured by various drugs, the tubules are a common target [1,2,3▪,4–6]. As such, acute tubular injury underlies much of drug-induced AKI, which occurs by various mechanisms. In addition to underlying patient susceptibility to kidney injury (Table 1), the inherent nephrotoxicity of drugs and the renal handling (transport and metabolism) of medications result in acute tubular injury [1,2,3▪,4–6].
Metabolism of numerous medications occurs in the liver, gastrointestinal tract, and kidneys, whereas excretion of drugs and metabolites may be either extrarenal or by the kidneys [1,2,3▪,4–6]. Focusing of renal excretion, the two major pathways mediate drug clearance – glomerular filtration or tubular secretion (or some combination of the two pathways). As such, tubular cells (and the surrounding interstitium) are exposed to potentially nephrotoxic medications via apical contact and cellular uptake or transport from the basolateral circulation through cells with subsequent apical efflux into the urine [1,2,3▪,4–6]. As drugs move from the proximal tubular lumens into the loop of Henle and distal tubular lumens, there is potential for tubulointerstitial injury. Injury in these more distal nephron sites can occur due to precipitation of drug crystals within tubular lumens and formation of drug-containing obstructive casts [7,8,9▪▪]. Tubulointerstitial injury from drug-related inflammatory injury is another mechanism of AKI induced by various medications .
Drug-induced proximal tubular injury, as will be discussed, may be caused by various mechanisms (mitochondrial injury, oxidative injury, DNA damage) that lead to apoptosis, necrosis, and other modes of cell death [11–29]. Drugs can promote proximal tubular injury without AKI (isolated proximal tubulopathy), AKI, or combined AKI and a proximal tubulopathy. Clinically, proximal tubulopathy presents with hypokalemia, hypophosphatemia, or full blown Fanconi syndrome, whereas isolated AKI often is complicated by hyperkalemia and hyperphosphatemia. Combined AKI and proximal tubulopathy can present with low, normal, or elevated serum electrolytes. Fanconi syndrome and partial proximal tubulopathy are often reversible with recovery generally taking up to several months, but can be permanent in rare cases. The mechanisms underlying the decline in glomerular filtration rate (GFR) seen with tubular injury is not definitely known but is likely due to a combination of afferent arteriole vasoconstriction (tubuloglomerular feedback), tubular back leak of filtrate, and tubular obstruction from apoptotic/necrotic cells and proteins . Kidney function recovers in some, but not all patients. This may be due to disturbed remodeling from inflammation, with tubular atrophy and interstitial fibrosis.
PROXIMAL TUBULAR INJURY VIA APICAL DRUG TRANSPORT
Drug or metabolite entry into the proximal tubular luminal space following filtration exposes the apical surface of tubular cells to various nephrotoxins. Uptake into tubular cells occurs for medications such as the aminoglycosides, various complex sugars and starches, and a number of heavy metals [2,3▪]. For the cationic aminoglycosides, their positive charge attracts these drugs to the negatively charged apical membrane, which is due to negatively charged membrane phospholipids [2,3▪,11–14]. The drugs then bind the endocytic receptor complex, megalin–cubilin, where they are translocated into the lysosomal compartment (Fig. 1). This apical pathway of uptake leads to accumulation of a critical concentration of aminoglycoside within cells, which triggers an injury cascade leading to cell injury and death, which present clinically as a proximal tubulopathy and/or full blown AKI [2,3▪,11–14]. Injury is primarily due to lysosomal accumulation and formation of myelin bodies, which are membrane fragments and damaged organelles formed as a consequence of aminoglycoside inhibition of lysosomal enzymes [2,3▪,13–16].
In contrast to endocytic uptake by the megalin–cubilin complex, filtered complex sugars and such as dextran and sucrose, and starches such as hydroxyethyl starch undergo pinocytosis by proximal tubular cells [2,3▪,13,17,18]. Similar to the aminoglycosides, following pinocytosis these substances are taken up by and collect in lysosomes (Fig. 2). Lysosomal and cytoplasmic accumulation occurs in part due to the absence of cellular enzymes capable of metabolizing these substances [2,3▪,17,18]. Ultimately, this buildup of hydroxyethyl starch causes acute tubular cell injury and AKI, resulting in what is known as ‘osmotic nephropathy’ [2,3▪,17,18]. Histologically, the lesion is characterized by the presence of swollen, vacuolated cells that compromise and occlude proximal tubular lumens [17,18] (Fig. 3).
PROXIMAL TUBULAR INJURY VIA BASOLATERAL DRUG TRANSPORT
In contrast to drugs that are filtered and enter proximal tubular cells through apical uptake (endocytosis and pinocytosis), several medications enter the urine through transport from the basolateral circulation [2,3▪,19–23]. Delivery of potentially nephrotoxic drugs by the peritubular capillaries, followed by uptake into proximal tubular cells occurs via a family of active transporters which is the first step of renal excretion [2,3▪,19–23]. A number of basolateral transporters exist including two prominent drug transporters – the human organic anion (hOAT) for negatively charged drugs and the human organic cation transporters (hOCT) for positively charged drugs [2,3▪,19–23]. However, not only medications are transported via these transporters; endogenously produced anionic and cationic substances compete for transport by these pathways.
Tenofovir dysproxil fumarate, a known nephrotoxin, is an acyclic nucleotide phosphonate that is transported by hOAT-1 (Fig. 4) [2,3▪,19]. Once inside the tubular cellular cytoplasm, tenofovir moves through the intracellular space by various regulated carrier proteins, finally engaging apical efflux transporters (multidrug resistant protein, P-glycoprotein) to exit into the urinary space [2,3▪,19]. By virtue of this transport pathway, tenofovir may lead to acute tubular injury when efflux out of cells is blunted (loss of function mutations in efflux transporters or competition from other endogenous substances) or transport into the cell is increased (as with enhanced basolateral transport in setting of reduced GFR), which promotes an increase in intracellular drug concentrations [2,3▪,19]. As tenofovir is a mitochondrial toxin, elevated levels enhance mitochondrial dysfunction and ultimately acute tubular cell injury from apoptosis and necrosis.
Similarly, cisplatin, which is transported into the cell cytoplasm via hOCT-2 is shuttled through the cell by carrier proteins to efflux transporters (human multidrug and toxin extrusion proteinh) prior to urinary excretion (Fig. 5) [2,3▪,22–26]. As with tenofovir, reduced transport out of the cell or increased cell entry can lead to proximal tubular injury and AKI. Increased intracellular cisplatin is associated with the formation of reactive thiol compounds and monohydroxyl complexes that are highly toxic to the proximal tubular cell [27–29]. Toxic tubular injury is mediated through oxidative stress, reactive nitrogen species, and induction of proapoptotic and inflammatory pathways. Reactive oxygen species (ROS) directly affect protein synthesis and structure, DNA synthesis and cell repair mechanisms, while increased TNF-α, transforming growth factor-beta, and monocyte chemoattractant protein-1 are also toxic to the cell [27–29]. In fact, TNF-α has a central role in inducing cisplatin-mediated cell injury by inducing apoptosis, ROS, and production of multiple cytokines in the kidney [27–29]. For both drugs, extensive trafficking of these agents increases tubular exposure and risk for elevated concentration of potentially nephrotoxic drugs when other risk factors supervene.
CRYSTALLINE-INDUCED TUBULAR INJURY
Various drugs and their metabolites excreted by the kidneys are insoluble in the urine causing a ‘crystalline nephropathy’ [7,8,31]. Medications include methotrexate, indinavir (Fig. 6), acyclovir, atazanavir, sulfadiazine, ciprofloxacin, triamterene, and oral sodium phosphate. Reduced urinary flow rates, excessive drug dosing, and rapid infusion rates increase drug/metabolite insolubility within tubular lumens [2,3▪,7,8,31]. For example, true and effective volume depletion promotes kidney hypoperfusion and prerenal physiology, which enhances nephrotoxicity in by fostering drug overdosing and enhancing drug/metabolite crystal precipitation within distal tubular lumens in the setting of sluggish urinary flow rates of insoluble drugs [2,3▪,7,8,32,33]. In addition, metabolic disorders that alter urinary pH, depending on the drug pKa, also increase risk for intratubular crystal deposition with certain drugs [2,3▪,7,8,32,33]. Urine pH less than 5.5 increases intratubular crystal deposition with drugs such as sulfadiazine, methotrexate, and triamterene, whereas urine pH more than 6.0 increases crystal precipitation within tubular lumens from drugs such as indinavir, atazanavir, and ciprofloxacin [2,3▪,7,8,31–33]. As a result of crystal precipitation within the distal tubular lumens, tubular flow is obstructed and a surrounding interstitial inflammatory response develops leading to kidney injury. This section will focus on methotrexate as a cause of drug-induced crystalline nephropathy.
Methotrexate is an effective anticancer agent when administered in high dose (>1 g/m2) [27,28]. The overall incidence rate of AKI is approximately 2% with a range 0–12%, which depends on population studied and AKI definition employed [27–34]. As noted above, AKI develops due to precipitation of parent drug and its metabolites within tubular lumens [27–35]. Two major risk factors for this to occur are true or effective volume depletion and the presence of an acidic urine. In addition to intratubular crystal deposition, methotrexate has been shown to induce formation of oxygen radicals with subsequent cellular injury, associated with decreased adenosine deaminase activity , which may also contribute to kidney injury. When AKI develops, urine microscopy often demonstrates renal tubular epithelial cells and granular casts. Drug crystals (alone and as crystalline casts) may be visible in the acidic urine, but are unlikely to be observed in an alkaline pH. Excessive methotrexate levels and systemic end organ toxicity often follows severe AKI.
DRUG-INDUCED CAST NEPHROPATHY
Vancomycin is a widely employed glycopeptide antibiotic for a variety of infections. Over 50 years ago, vancomycin was considered a ‘nephrotoxin’ and was nicknamed ‘Mississippi Mud’ because the early preparations were brown color, due to impurities . However, in the 1970s, development of newer vancomycin formulations with improved purity led to a great uptick in vancomycin use as an effective agent for many microbes, including methicillin-resistant Staphylococcus species . Nowadays, while generally well tolerated, vancomycin has been associated with increasing rates of AKI with incidence rate estimates of 5–20% [38,39]. Vancomycin-associated AKI occurs more commonly in high-risk patients (underlying chronic kidney disease, obesity, etc.), with excessive serum levels, high doses/prolonged duration of therapy, use in critically ill patients, and when combined with other drugs such as piperacillin–tazobactam and aminoglycosides [2,3▪,38,39,40▪▪,41].
Vancomycin is excreted primarily by the kidneys and is thought to enter the urinary space by both glomerular filtration and active tubular secretion [9▪▪,38,39,40▪▪,41]. The mechanism of vancomycin-associated nephrotoxicity is not definitely known but various possible pathways of nephrotoxicity exist. Dose-dependent nephrotoxicity by this antibiotic includes induction of oxidative stress, complement activation with inflammatory injury and mitochondrial damage . These injury pathways lead primarily to acute tubular injury/necrosis. Acute tubulointerstitial nephritis (ATIN) is another mechanism of vancomycin-induced AKI .
A new, unique mechanism of vancomycin-related kidney injury that was recently described is a form of drug-induced obstructive tubular cast formation [9▪▪]. Patients that underwent kidney biopsy for AKI in the setting of vancomycin therapy were studied. Immunohistologic staining techniques were employed to detect vancomycin in kidney tissue in these patients; obstructing tubular casts composed of noncrystal, nanospheric vancomycin aggregates entangled with uromodulin were noted [9▪▪]. The casts were reminiscent of ‘myeloma light chain casts’ as they had a monocytic, cellular reaction around them. High vancomycin trough plasma levels, some with concomitant nephrotoxin exposure, were seen in the patients. Similar vancomycin casts were reproduced experimentally in mice. Thus, the interaction of nanospheric vancomycin aggregates with uromodulin to form obstructing casts may represent another form of acute tubular injury with exposure to excessive vancomycin levels [9▪▪].
DRUG-INDUCED ACUTE TUBULOINTERSTITIAL NEPHRITIS
Drug-induced ATIN is thought to be primarily a T-cell-mediated type-4 delayed hypersensitivity reaction, although immune-complex deposition (antitubular basement membrane antibody) and direct unprocessed drug interaction with T cells leading to T-cell activation may also play a role in drug hypersensitivity . The kidneys are particularly sensitive to drug hypersensitivity, in part due to high renal blood flow and local drug metabolism, leading to ATIN. The pathogenesis of drug-induced ATIN is generally divided into four phases . The antigen recognition phase begins with drugs within the kidneys rendering renal tissue antigenic by acting as prohaptens or haptens, by damaging native renal proteins and turning them into ‘neo-antigens’, or through molecular mimicry. Upon formation of antigenic kidney tissue, resident dendritic cells, renal tubular epithelium, and interstitial macrophages subsequently function as antigen presenting cells . Disturbance of the immune regulation phase in the kidney occurs with drug-induced ATIN, with drugs like the immune-checkpoint inhibitors reducing immune tolerance in the kidney. Finally, the effector phase in drug-induced ATIN is characterized by renal infiltration with lymphocytes, macrophages, eosinophils, mast cells, and other cells, which cause tubulointerstitial inflammation and injury (Fig. 7) . ATIN due to immune checkpoint inhibitors (ICPIs) will be discussed in this section.
The ICPI drugs are a novel cancer immunotherapy that consists of cytotoxic T-lymphocyte associated protein-4 receptor antibodies (ipilimumab, tremelimumab-not approved), program death-1 receptor antibodies (nivolumab, pembrolizumab), and program death ligand-1 (PD-L1) ligand antibodies (atezolizumab) [44▪▪,45,46,47▪,48▪▪]. These drugs are associated with a number of immune-mediated kidney lesions; however, ATIN is the most common. The exact mechanism underlying the development of ATIN has not been fully delineated. Formation of new or reactivated T cells against tumor antigens that cross-react with off-target kidney tissues is one possibility. Treatment with these drugs may reprogram the host's immune system that leads to loss of tolerance against off-target kidney antigens and development of ATIN [44▪▪,45,46]. For example, blocking T-cell program death-1 receptor from binding PD-L1 expressed on renal tubular cells. This mechanism may explain the long latency from ICPI exposure to AKI in published case reports [45,46,47▪,48▪▪]. Reactivation of drug-specific T cells through loss of tolerance caused by the ICPIs may reactivate drug-specific T cells thereby reducing normal host tolerance to other concomitantly prescribed medications (antimicrobials, NSAIDs, proton pump inhibitors) associated with ATIN, thereby precipitating this inflammatory kidney lesion [44▪▪,45,46,47▪,48▪▪]. An increase in proinflammatory cytokines and chemokines such as IL-1Ra, CXCL10, and TNF-α within kidney tissue may ATIN [44▪▪]. Finally, generation of autoantibodies (antikidney tissue antibodies) targeting renal tissue may also leads to development of immune-complex-related ATIN. This mechanism of ICPI-induced ATIN is actively being studied by several groups.
Drug-associated AKI can develop from a variety of mechanisms. Underlying patient susceptibility to drug toxicity plays an important role in AKI, however, the inherent nephrotoxicity of drugs and the transport and metabolism of medications by the kidneys are critical in the development of acute tubular injury. In the proximal tubules, apical transport of the aminoglycosides by megalin–cubilin endocytosis and basolateral transport of tenofovir and cisplatin by organic anion and cation transporters, respectively, increase risk for acute tubular injury. Proximal tubular pinocytosis of filtered hydroxyethyl starch with accumulation within lysosomes promotes acute tubular dysfunction. Precipitation of drug (and their metabolite) crystals within distal tubular lumens may occur with several drugs and lead to AKI. The anticancer agent methotrexate is one such example. Drug-associated cast nephropathy recently described with vancomycin represents a new mechanism of drug-induced AKI. Finally, ICPIs are an important, new cancer immunotherapy that is associated with ATIN (and other immune-related kidney lesions). Clinicians should be aware of the various pathways of kidney injury cause by commonly employed medications.
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Conflicts of interest
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REFERENCES AND RECOMMENDED READING
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