Critical Care Nephrology

and Acute Kidney Injury

Drug-Induced Acute Kidney Injury

Mark A. Perazella1,2 and Mitchell H. Rosner3

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 1
tubules contribute further to AKI. Drug-induced AKI may also develop through induction of inflammation Section of Nephrology,
Yale University School
within the tubulointerstitium. Medications can elicit a T cell–mediated immune response that promotes the of Medicine, New
development of acute interstitial nephritis leading to AKI. Although less common, a third pathway to kidney Haven, Connecticut
2
injury results from the insolubility of drugs in the urine leading to their precipitation as crystals within distal Veteran’s Affairs
tubular lumens, causing a crystalline-related AKI. Intratubular obstruction, direct tubular injury, and Medical Center, West
Haven, Connecticut
localized inflammation lead to AKI. Clinicians should be familiar with the pathogenesis and clinical- 3
Division of
pathologic manifestations of these forms of kidney injury. Prevention and treatment of AKI relies on Nephrology, University
understanding the pathogenesis and judiciously using these agents in settings where AKI risk is high. of Virginia Health
System, Charlottesville,
CJASN 17: 1220–1233, 2022. doi: https://doi.org/10.2215/CJN.11290821
Virginia

Introduction tubular injury. Advanced age, preexisting kidney dis- Correspondence:

Dr. Mark A. Perazella,
Medications are a relatively common cause of AKI in ease, and true or effective intravascular volume deple- Section of Nephrology,
hospitalized patients and those in the intensive care tion are important risk factors (Table 3). Yale University School
unit (1,2). Depending on the definition employed, of Medicine, New
drugs are associated with AKI in 14%–26% of adults Haven, CT 06520.
Select Medications and Pathogenesis Email: mark.perazella@
in prospective cohort studies (1,2) and 37.5% in a Cidofovir and tenofovir, nucleoside analogs with yale.edu
cross-sectional survey (3). Importantly, medications activity against viral reverse transcription, are associated
are also a common cause of AKI in children. Although with dose-dependent AKI in 12%–24% of patients (5,6).
medications induce various forms of kidney injury, Tenofovir alafenamide (versus tenofovir disoproxil) is
drug-induced injury to the tubulointerstitial compart- less nephrotoxic due to its conversion to active drug in
ment is a common cause of AKI (4). Several medica- lymphocytes, resulting in much lower plasma levels.
tions cause acute tubular injury in at-risk hosts due to Urinary abnormalities resembling Fanconi syndrome
their innate toxicity and kidney handling (4). Drug- with proteinuria, glucosuria, and variable bicarbonate
induced acute interstitial nephritis (AIN) also occurs wasting develop due to proximal tubular injury (7).
when medications elicit a T cell–mediated immune Tubular dysfunction, which may precede AKI, occurs in
response that promotes tubulointerstitial inflamma- part because 20%–30% of drug is actively transported
tion. A third pathway of injury results from the insol- into proximal tubule cells by organic anion transporters
ubility of drugs in urine leading to their intratubular (hOAT1.OAT3) in basolateral membranes (8,9) (Figure
precipitation as crystals with an associated inflamma- 1). Subsequently, the drug is secreted into the tubular
tory response. Pseudo-AKI caused by drugs that block lumen by multidrug resistance proteins (MRP2 and
tubular creatinine secretion as well as hemodynamic MRP4), which are apical membrane transporters (7,9).
causes of increases in serum creatinine should be con- Once within the mitochondrial-rich cells, these drugs
sidered in patient evaluation. Table 1 lists the drugs decrease mitochondrial DNA content by inhibiting mito-
associated with increased serum creatinine due to chondrial DNA polymerase-g, leading to structural
pseudo- and hemodynamically mediated AKI and the changes in mitochondria that result in apoptosis and
putative mechanisms. AKI (10–12). Given the importance of proximal tubule
transport of these agents, certain drugs that block
hOAT1 and cellular uptake (probenecid) may decrease
Acute Tubular Injury nephrotoxicity (13–15). In contrast, drugs such as non-
Direct tubular injury, which occurs with different steroidal anti-inflammatory drugs (NSAIDs) that block
classes of drugs such as antimicrobial agents, chemo- apical tenofovir efflux through MRP4 increase kidney
therapeutic drugs, calcineurin inhibitors, and contrast injury (13–15). The most effective treatment of
agents (Table 2), is a common cause of AKI (4). Expo- tenofovir-related acute tubular injury is early drug dis-
sure to multiple nephrotoxins and underlying comor- continuation, which enhances resolution of tubular dys-
bid medical conditions increase the likelihood of function. Approximately 50% of patients completely

1220 Copyright © 2022 by the American Society of Nephrology www.cjasn.org Vol 17 August, 2022
CJASN 17: 1220–1233, August, 2022 AKI Associated with Common Medications, Perazella and Rosner 1221

Table 1. Medications associated with pseudo-AKI and hemodynamically mediated AKI

Medications Associated
Medications Associated Mechanism of Increased
with Hemodynamically Mechanism of Reduced GFR
with Pseudo-AKI Serum Creatinine
Mediated AKI
 Cimetidine Decrease creatinine secretion  Angiotensin-converting Inhibit efferent arteriolar
 Trimethoprim through the proximal enzyme inhibitors and vasoconstriction and
 Dronedarone tubular cells into the urine angiotensin receptor reduce GFR
 Cobicistat and dolutegravir blockers
 Tyrosine kinase inhibitors
(imatinib, bosutinib,
sorafenib, sunitinib,
crizotinib, gefitinib, and
pazopanib)
 Pyrimethamine
 Dexamethasone Some formulations contain  NSAIDS Inhibit production of
creatinine as an excipient vasodilatory
prostaglandins with
afferent arteriolar
vasoconstriction
(especially prominent in
states of volume
depletion, older age,
hypercalcemia and
effective arterial volume
depletion such as
cirrhosis, heart failure,
nephrotic syndrome)
 Cefoxitin Recognized as a creatinine  SGLT2 inhibitors Induce vasoconstriction of
chromagen by the alkaline the afferent arteriole due
picrate method of to tubuloglomerular
creatinine analysis feedback
 Flucytosine Interferes with enzymatic  Calcineurin inhibitors Induce vasoconstriction of
assay for serum creatinine the afferent arteriole (due
determination to an imbalance between
vasoconstrictor agents
such as endothelin,
thromboxane, and
activation of the renin-
angiotensin system and
decrease of vasodilator
factors like prostaglandin
E2, prostacyclin, and
nitric oxide)
 Corticosteroids Catabolic state with release
of creatine from muscle,
which is converted to
creatinine
 Calcitriol and alfacalcidol Unclear
 Fenofibrate Increase metabolic
production of creatinine

NSAIDS, nonsteroidal anti-inflammatory drugs; SGLT2, sodium-glucose cotransporter 2.

recover kidney function to baseline levels over weeks to mitochondrial injury with development of cell apoptosis/
months after AKI (16,17). necrosis (Figure 1) (19). Death and inflammation of proxi-
Aminoglycosides, including tobramycin, gentamicin, mal tubular cells as well as nonlethal, functional changes in
amikacin, and others, are associated with AKI in 10%–25% tubular handling of electrolytes inducing Fanconi and
of exposed patients. AKI risk factors include prolonged Bartter-like syndromes are seen (23–26). Gentamicin can
duration of therapy, concomitant nephrotoxin exposure, also reduce renal blood flow and lead to kidney parenchy-
and a variety of comorbidities (18,19). Gentamicin, the most mal ischemia, which can further potentiate nephrotoxic
commonly prescribed aminoglycoside, is largely removed acute tubular injury (27). Patients develop nonoliguric AKI,
by glomerular filtration, with 10%–20% of drug undergoing usually 5–7 days after initiation of therapy, with variable
endocytosis via megalin-cubilin receptors into S1/S2 seg- degrees of polyuria and hypomagnesemia (28). Drug cessa-
ment proximal tubular cells (20–22). Drug then accumulates tion is often associated with kidney recovery; however,
in lysosomes causing structural injury and myeloid body chronic changes can develop with prolonged therapy (29).
formation, as well as in Golgi and endoplasmic reticulum Vancomycin is a widely prescribed antibiotic that is asso-
leading to cell injury. After destabilization of intracellular ciated with AKI. Although the exact nature of vancomycin-
membranes, drug enters the cytoplasm and promotes associated nephrotoxicity is unclear, it is likely that acute
1222 CJASN

Table 2. Medications associated with acute tubular injury and preventative strategies

Medication Class Individual Medications Preventative Strategiesa

Antibiotics Aminoglycosides (gentamicin, neomycin,  Once daily dosing
amikacin)  Adjust dose for underlying eGFR
 Use tobramycin over gentamicin if
possible
Vancomycin (1/2 piperacillin-  Adjust dose for underlying eGFR
tazobactam)  Therapeutic drug monitoring
(maintain trough concentrations ,15
ng/ml)
 Avoid combination with piperacillin-
tazobactam
 Use alternative agents
Colistin/polymyxins  Adjust dose for underlying eGFR
 Avoid prolonged use
 Use alternative agents
Antifungals Amphotericin B products  Use lipid or liposomal forms
 iv isotonic crystalloid hydration
Antiviral agents Cidofovir, tenofovir, adefovir  Adjust dose for underlying eGFR
 Screen for tubular toxicity to identify
early injury
 Use alternative agents
Foscarnet  Use alternative agents
Analgesics NSAIDs including COX-2 inhibitors  Avoid use in high-risk patients
Acetaminophen overdose  Avoid excessive dosing especially in
liver disease
Chemotherapeutic agents Cisplatin (less common with other platin  Adjust dose for underlying eGFR
analogs)  iv isotonic crystalloid–induced
diuresis
 Use of lower-dose regimens
 Use of cisplatin analogs
 Consider sodium thiosulfate in high-
risk patients
Ifosfamide  Adjust dose for underlying eGFR
 Limit dose
 Mesna and N-acetylcysteine of
unproven efficacy
Pemetrexed  Adjust dose for underlying eGFR
 Avoid in patients with eGFR,45 ml/
min per 1.73 m2
Radiocontrast agents Iodinated radiocontrast agents  iv isotonic crystalloid hydration
 Low or iso-osmolar contrast agents
Calcineurin inhibitors Cyclosporine, tacrolimus  Reduce dose and follow drug levels
 Consider alternative agents such as
mTOR inhibitors
Bisphosphonates Pamidronate  Lengthen infusion times to .2 h
 Use lower doses
 Use alternative agents such as
denosumab
Zolendronic acid  Use lower doses especially if
eGFR,60 ml/min per 1.73 m2
 Contraindicated in AKI and eGFR,30
ml/min per 1.73 m2
 Use alternative agents such as
denosumab

iv, intravenous; NSAIDs, nonsteroidal anti-inflammatory drugs; COX, cyclo-oxygenase; mTOR, mammalian target of rapamycin.
a
Volume expansion to correct hypovolemia and enhance tubular flow is recommended as prevention for many of the drugs noted
in this table.

tubular injury plays a significant role (30). The rate of AKI vancomycin levels. However, this may just reflect AKI
with use of modern vancomycin preparations varies from from other causes limiting vancomycin excretion by the
as low as 0% in the absence of concurrent nephrotoxins to kidneys. Mechanistically, vancomycin induces reactive
.20% when administered in more complex settings such oxygen species, which may affect cell metabolism and
as with piperacillin-tazobactam (31,32). Epidemiologically, various enzymatic activities. Vancomycin may also
the incidence of vancomycin-associated AKI increased increase mitochondrial stress, releasing cytochrome-c and
when experts raised target trough levels for complicated activating the caspase pathway, resulting in cellular stress
infections to 15–20 mg/L (32). This fits the observation and apoptosis (30,32). The role of vancomycin casts,
that AKI is most often associated with supratherapeutic which are noncrystalline vancomycin aggregates with
CJASN 17: 1220–1233, August, 2022 AKI Associated with Common Medications, Perazella and Rosner 1223

APICAL PROXIMAL TUBULE BASOLATERAL

MC
AG NaDC

hMATE1

MRP2 OAT-1
TF

MRP4
ATP-ase
Mitochondrion

Pgp
Swollen, distorted Na+ K+
mitochondrion

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 substan-
ces (TNF-a, TGF-b, and ROS), which promote mitochondrial toxicity. Tenofovir (blue) is delivered to the basolateral membrane, trans-
ported 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 trans-
porter; hOAT1, human organic anion transporter; hOCT2, human organic cation transporter–2; K1, potassium; MC, megalin-cubilin; MRP,
multidrug resistance protein transporter; Na1, sodium; NaDC, sodium dicarboxylate transporter; Pgp, P-glycoprotein transporter; ROS,
reactive oxygen species; TF, tenofovir.

uromodulin, may contribute to AKI by obstructing tubu- AKI typically occurs 5–7 days after therapy, whereas
lar lumens (33). AKI generally occurs after 4–8 days of dialysis-requiring AKI is uncommon in the absence of con-
therapy, and drug withdrawal improves kidney function comitant nephrotoxic exposures. AKI typically resolves
in most patients (30). within a few weeks, but progressive CKD associated with
Cisplatin and other platinum-based agents are effective tubulointerstitial fibrosis may occur (47). Tubular injury
chemotherapeutic agents; however, both acute and cumula- with cisplatin may also be associated with kidney magne-
tive nephrotoxicity can limit their use. Cisplatin elimination sium wasting, Fanconi-like syndrome, distal renal tubular
occurs via basolateral proximal tubular cell organic cation acidosis, and salt wasting (47–50).
transport pathways, whereupon the drug enters cells, is Ifosfamide is a structural isomer of cyclosphosphamide
shuttled to the apical membrane efflux transporter that is an effective cancer therapy. However, drug-
(hMATE1) via carrier proteins, and secreted into the urine induced acute tubular injury can occur with cumulative
(Figure 1). The proclivity for proximal tubule toxicity is dosing and previous cisplatin exposure. Importantly,
likely related to the key role of organic cation transporter–2 ifosfamide-associated proximal tubulopathy is more com-
and variable roles of OAT1 and OAT3 in cisplatin handling mon than AKI. Similar to cisplatin, ifosfamide enters prox-
(34–37). Cytotoxicity develops due to multiple injury mech- imal tubular cells via organic cation transporter–2, and one
anisms including crosslinking of DNA strands, generation of its metabolites, chloroacetaldehyde, is likely the cause
of reactive oxygen species, vasoconstriction leading to of tubular injury (51). The mechanism whereby chloroace-
ischemia, activation of inflammatory pathways, and pro- taldehyde causes injury is not proven but may be due to
duction of various caspases and cytokines such as TNF-a, mitochondrial injury from oxidative stress (52). Clinically,
IL-6, and IFN-g (38–43). Key risk factors for nephrotoxicity ifosfamide toxicity is expressed with proximal tubule dys-
include higher peak concentrations of cisplatin, previous function (partial/complete Fanconi syndrome), nephro-
cisplatin exposure, preexisting kidney disease, and con- genic diabetes insipidus, and AKI. The decline in GFR is
comitant nephrotoxin exposure (44–46). Cisplatin-induced usually modest unless ifosfamide is coadministered with
1224 CJASN

Table 3. Common risk factors for drug-induced acute tubular injury

Modifiable Risks Nonmodifiable Risks
Volume depletion and/or hypotension Advanced age especially with concomitant CKD
Exposure to concomitant nephrotoxins (eGFR,45 ml/min per 1.73 m2)
High-level exposure to nephrotoxins (high-dose and long- Comorbid conditions such as liver disease, diabetes mellitus,
duration therapy) heart failure, major surgery (especially cardiovascular)
Excessive medication dose for underlying GFR High-risk settings such as intensive care unit, burn unit,
cardiovascular care unit
Shock states such as sepsis
Solid organ transplantation
Stem cell transplantation
Genetic vulnerability

other nephrotoxins, especially cisplatin (53). Given that rifampin, and the fluoroquinolones are common causes of
most recipients of ifosfamide are young, there is concern antibiotic-associated AIN. AIN associated with these drugs
about long-term tubular effects, but limited data suggest classically leads to rapid AKI onset and may be associated
that the majority of patients have normal kidney function with typical allergic features. This presentation often leads
several years later (54). to early diagnosis and treatment of AIN resulting in
Other medications that cause acute tubular injury improved kidney recovery in most patients (56,63).
through direct toxicity such as amphotericin B (including NSAIDs are another relatively common cause of drug-
liposomal preparations), the polymyxins, zolendronic acid, induced AIN, accounting for 10%–15% of all cases (56). In
and pemetrexed are described in Table 2. contrast to antibiotics, NSAID-related AIN often presents
many weeks or months after drug initiation and does not
Prevention and Treatment manifest typical allergic manifestations, making clinical
There are no specific therapies for acute tubular injury diagnosis challenging and increasing the need for kidney
and, thus, therapy is largely conservative and focused on biopsy.
stopping offending agents, avoiding further kidney injury PPIs are another important cause of AIN with an inci-
by maximizing kidney perfusion with intravenous fluids, dence estimated to be 0.8–3.2/10,000 person-years of expo-
and avoiding nephrotoxins. Given the lack of effective thera- sure (64,65). In patients .65 years of age and newly started
pies, prevention is critical and several nephrotoxin-specific on PPIs, the overall incidence of AIN was 3.2/10,000
strategies to lower the risk of AKI have been investigated person-years in PPI users compared with 1.1/10,000
(Table 2). In addition, recognition of clinical scenarios of person-years in propensity-matched controls (64). How-
high risk is critical in alerting clinicians to the need for avoid- ever, many PPI-associated AIN cases may be overlooked
ance of nephrotoxic agents (Table 3). Recognition of the early due to lack of allergic symptoms and delayed development
signs of tubular injury utilizing sensitive biomarkers may of AIN. In fact, well-controlled studies demonstrated that
also hold future promise to predict early kidney injury and long-term PPI use was associated with a 36% and 42%
allow cessation of potential nephrotoxins (55). higher risk of CKD and kidney failure, respectively, pre-
sumably from unrecognized AIN (66–69).
ICPIs are a newly recognized cause of AIN (60,70–72).
Acute Interstitial Nephritis They include inhibitors of the immune checkpoints CTLA-
Acute interstitial nephritis (AIN) is an immune-mediated 4, PD-1, and PDL-1. The incidence of ICPI-related AIN is
form of kidney injury that is characterized histologically by unknown; however, AKI due to these drugs is estimated at
infiltration of immune cells in the tubulointerstitium (56). 2%–5% (60,71). In a multicenter study of 429 patients on
AIN is observed in approximately 15% of biopsies performed ICPIs that developed AKI, biopsy-proven AIN was noted
for evaluation of AKI (56–58). These numbers, however, may in 83% of 151 patients (59). Approximately 70% of patients
underestimate the true incidence of AIN. Many patients, par- were receiving another AIN-inducing medication such as
ticularly those in intensive care units, are often incorrectly PPIs. AKI occurred at a median of 16 weeks (interquartile
presumed to have tubular injury because they lack sugges- range, 8–32 weeks) after drug initiation, with risk factors
tive allergic features and do not undergo biopsy. Medications including prior or concomitant extrarenal immune-related
are the most common cause of AIN, estimated to cause adverse event, lower baseline eGFR, and PPI coadministra-
.70% of AIN observed in high-income countries (56,57). tion (59). ICPI discontinuation and corticosteroids resulted
in recovery of kidney function in 64.3% at a median of 7
Select Medications weeks after diagnosis. An important issue is whether it is
Over 120 drugs are reported to cause AIN (Table 4); safe to rechallenge patients with these drugs after a bout of
however, antibiotics, NSAIDs, proton pump inhibitors AKI. ICPI rechallenge was associated with AKI recurrence
(PPIs), and immune-checkpoint inhibitors (ICPIs) are the in 20 of 121 patients (16.5%) at a median of 10 weeks (59).
most common culprits (56,57,59–61). This suggests that re-exposing patients after a bout of AKI
Antibiotics were one of the earliest medications as- can be done safely in most patients.
sociated with AIN and account for nearly half of all AIN Establishing the diagnosis of drug-induced AIN in the
cases (56,62). b-Lactam antibiotics, sulfa-containing drugs, absence of kidney biopsy is a challenge. Suspicion is raised
CJASN 17: 1220–1233, August, 2022 AKI Associated with Common Medications, Perazella and Rosner 1225

Table 4. Medications associated with acute interstitial nephritis

Medication Class Individual Medications

Antibiotics b-Lactam drugs (penicillin and derivatives, cephalosporins)
Sulfa-based antimicrobials (trimethoprim-sulfamethoxazole, sulfadiazine)
Fluoroquinolones
Macrolides
Rifampin
Antiacid GI drugs Proton pump inhibitors (class effect for all agents)
Histamine-2 blockers
Analgesics NSAIDs including COX-2 inhibitors (class effect for all agents)
Immunotherapies PD-1 inhibitors (nivolumab, pembrolizumab, cemiplimab)
PD-L1 inhibitors (atezolizumab, durvalumab, avelumab)
CTLA-4 inhibitors (ipilimumab, tremelimumab)
Antiangiogenesis drugs Bevacizumab, tyrosine kinase inhibitors (sorafenib, sunitanib)
Diuretics Loop diuretics (furosemide, bumetanide)
Thiazide diuretics (hydrochlorothiazide)
Antiviral agents Acyclovir
Abacavir
Indinavir
Atazanavir
Foscarnet
Anticonvulsants Phenobarbital
Carbamazepine
Phenytoin
Other agents Ifosfamide
Pemetrexed
Lithium
Allopurinol
Mesalamine and other 5-aminosalicylates

GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs; COX-2, cyclooxygenase-2; PD-1, programmed cell death
protein–1; PD-L1, programmed death–ligand 1; CTLA-4, cytotoxic T lymphocyte associated protein–4.

by exposure to a culprit medication in the setting of mimic an antigen that is normally present within the tubular
impaired kidney function. However, allergic features such basement membrane or interstitium, or deposit in the tubu-
as rash, fever, and eosinophilia are rare. Pyuria is seen in lointerstitium and behave like a planted antigen (Figure 2).
approximately half of the cases, whereas leukocyte casts Dendritic cells interspersed between tubular cells recognize
are rarely seen (73–75). The utility of urine eosinophils was these drug-related antigens, migrate to local lymph nodes,
examined in a single-center study where kidney biopsy and initiate adaptive immune responses (77–79). Immune-
specimens and urine eosinophils were obtained in 566 mediated kidney injury is orchestrated by various CD41 T
patients (57). At urine eosinophil cutoffs of 1%–5% and cell subsets and varies depending on the inciting agent, sug-
.5%, respectively, sensitivity and specificity were subopti- gesting that AIN may be the final common pathway of dis-
mal, making urine eosinophil testing an unhelpful bio- tinct mechanisms of injury (77–79).
marker (76). In contrast, novel cytokine urine biomarkers Despite widespread consumption of AIN-inducing medi-
(IL-9 and TNF-a) may offer a noninvasive diagnostic cations, AIN remains a relatively rare complication, sug-
option for AIN (77). gesting a role for patient-specific risk factors. Variations in
Kidney biopsy is often required to establish the diagnosis human leukocyte antigen loci were evaluated in 154
of drug-induced AIN. An interstitial inflammatory infiltrate patients with AIN and 200 healthy controls (78). In the
and tubulitis characterize AIN. The infiltrate consists pre- patients with drug-induced AIN, 58% had specific human
dominantly of CD41 and CD81 T lymphocytes (76), leukocyte antigen variants (DQA1*0104, DQB1*0503, and
although macrophages and B cells may also be observed. DRB1*1405) versus 7.5% of controls. These variants were
Eosinophils and occasionally granuloma may be seen on also associated with worse AKI and more severe tubuloin-
histology, especially with antibiotics. However, eosinophils terstitial infiltrate.
are frequently absent from NSAID-induced AIN. Medications appear to cause AIN through different path-
ways. In antibiotic-induced AIN, CD41 T cells that pro-
duced TH1 and TH2 cytokines (e.g., IFN-g, IL-4, IL-13) were
Pathogenesis isolated from both kidney tissue and peripheral blood (79).
Drug-induced AIN is considered primarily a T cell–driven TH1 cells can also lead to activation of proinflammatory
process that is often limited to the kidneys. High drug con- M1-type macrophages; an elevated urinary M1/M2 macro-
centrations within kidneys, local drug metabolism before phage ratio was noted in AIN patients (80). Patients with
excretion, or damage caused to tubular epithelial cells are PPI-induced AIN were observed to have TH17 cells as a
important factors (77–79). Drugs can bind to the tubular major part of the cellular infiltrate (81). Mast cells were also
basement membrane and act as haptens or prohaptens, noted in biopsy specimens of patients with drug-induced
1226 CJASN

Renal tubular epithelial cells

Hapten or prohapten
Medications Molecular mimicry
Planted drug antigen

Antigen presentation Antigen presenting cell

Lymph node
CD4+ naïve Antigen
IL-2 Th cells presentation
IFN-J
IL-2
CD4+
CD4+
Th1
Th9
CD4
IFN-J Th2 IL-9
IL-4
IL-5 IL-13

Macrophages CD8 T cells Eosinophils Macrophages Mast cells/basophils

Acute interstitial nephritis

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 CD41 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 base-
ment membrane; Th, T-helper. This figure was generously provided by Dr. Dennis Moledina, with permission.

AIN (82). Additionally, IL-9, a cytokine responsible for mast observational studies (62,83–89) (Table 5). In some but not
cell accumulation, was also elevated in AIN patients versus all studies, earlier corticosteroid therapy was associated
non-AIN controls (77). Prior use of AIN-inducing drugs with benefit (83,85). In 182 patients with biopsy-proven
such as PPIs are associated with a higher risk for AIN in AIN, no difference in kidney function recovery was
ICPI-treated patients, making reactivation of drug-specific T observed in longer versus shorter corticosteroid duration
cells due to loss of immune tolerance possible (59). (83). Furthermore, no differences in kidney function out-
comes were derived from high-dose intravenous corticoste-
Treatment roid versus 1 mg/kg oral prednisone (90).
In patients suspected of having drug-induced AIN, drug AIN can cause permanent kidney damage from ongoing
discontinuation is critical. Given the immune-mediated tubulointerstitial inflammation and fibrosis formation.
nature of kidney damage, corticosteroids are often Studies estimate that approximately 50% of patients
prescribed. However, corticosteroid dosing regimens are develop CKD after AIN (64,76,91–93). In fact, patients with
not standardized and vary widely. Outcome data consist AIN lost a median of 11 ml/min per 1.73 m2 of eGFR from
of positive and negative effects that are limited to baseline to 6 months after biopsy (94). Greater interstitial
CJASN 17: 1220–1233, August, 2022 AKI Associated with Common Medications, Perazella and Rosner 1227

fibrosis is associated with lower kidney function recovery,

CS-treated patient had better eGFR at 2 yr and less dialysis (5.1% versus 24.1%).
Worse kidney function in CS-treated versus control at biopsy (sCr 4.2 versus 3.3
whereas greater interstitial inflammation is associated with

CS-treated patients with complete recovery had shorter delay to CS (13 d) as

Kidney recovery at 6 mo: CS 58.5% versus 50% (NS); kidney recovery at last
F/U: CS 78% versus 65% (NS); kidney failure: CS 14.6% versus 20% (NS)
improved kidney function recovery and more dialysis dis-

CS-treated patients had superior kidney outcomes with early versus late CS

mg/dl). CS-treated patients had complete recovery (48%) versus control

Improved GFR with CS versus control (P,0.05). No difference in kidney
continuation (83,94,95). Corticosteroids were most benefi-
cial in patients with greater interstitial infiltrate, higher
eGFR before biopsy, and higher urine IL-9 levels (83,94).
Patients received CS late after diagnosis (median delay .3 wk)

Identifying patient subgroups that may benefit from cor-

ticosteroids is paramount. These include those with higher
compared with those without complete recovery (34 d)

Dose, duration, and time to CS initiation were variable

GFR at biopsy and histology with more infiltrate and less
fibrosis (86,87,94). Patients with brittle diabetes, advanced
Study Details

group (41%); final sCr not different at 1 yr

cancers, and severe infections may not be candidates for
corticosteroids due to their associated adverse effects.
Because kidney recovery occurs primarily within the first
outcomes on the basis of CS timing

month after diagnosis, we recommend oral corticosteroids

for approximately 4–6 weeks with rapid taper if no
response is seen (28,29,83,84). Other than corticosteroids,
immunosuppressive agents such as azathioprine and
mycophenolate mofetil have been employed on the basis of
limited data. In patients that failed corticosteroids, partial
recovery of kidney function was noted in eight of ten
patients with ICPI-induced AIN treated with infliximab (96).
therapy

Crystalline Nephropathies
Crystalline nephropathies are characterized primarily by
33 (median)
Follow-Up

CS, corticosteroids; NR, not reported; sCr, serum creatinine concentration; NS, not significant; F/U, follow-up.
(months)

the histologic finding of intratubular crystal deposition

12
19

19

12

24
6

(97,98). Medications are a well-described cause of this

entity and can cause AKI, although less commonly than
acute tubular injury and AIN (97–99). Identification of crys-
eGFR 24

tals within the kidneys should prompt a search for crystal-

No CS
Final sCr (mg/dl) or eGFR

NR

NR
1.6
3.7

3.4

1.5
(ml/min per 1.73 m2)

forming medications (97–99). Urine sediment examination

showing crystal-containing casts is a helpful noninvasive
diagnostic test and may eliminate need for biopsy (99).
eGFR 43
NR

NR
1.6
2.1

2.8

1.4
CS

Select Medications
A number of drugs are noted to cause crystalline
nephropathy (Table 6). Intrarenal crystal deposition occurs
primarily due to the kidney route of drug/metabolite
Peak sCr (mg/dl) or eGFR

excretion and enhanced drug supersaturation within urine.

eGFR 25
No CS
(ml/min per 1.73 m2)

3.16

4.43

Supersaturation of drugs with crystal-forming capacity

6.1
4.9

5.2

4.5
Table 5. Corticosteroid therapy in acute interstitial nephritis

occurs with volume depletion/dehydration, which lowers

urinary flow rates (97–101). In addition, excessive drug
dosing, which increases urinary drug concentrations,
eGFR 20.5

causes intratubular crystal deposition with several medica-

4.03

4.67
7.9
5.9

6.5

3.0
CS

tions (97–101). Urine pH also influences supersaturation

depending on the pK of the drug in question (97–100).
Examples include acid pH for methotrexate and sulfadia-
No CS

zine and alkaline pH for indinavir, atazanavir, and cipro-

Sample Size

16

12

12

51

29

20
9

floxacin (97–100). The presence of underlying kidney dis-

ease may further enhance risk for drug-induced crystalline
nephropathy (97–100).
158
CS

26
52

37

83

73

82

Clinical presentation and laboratory findings, in particu-

lar urine microscopy, can be helpful for diagnosis of
Prendecki et al. 2016 (86)
Gonzalez et al. 2008 (85)
Clarkson et al. 2004 (89)

Muriithi et al. 2014 (73)

Valluri et al. 2015 (87)

drug-induced crystalline nephropathies (100,102). Not

Raza et al. 2012 (84)

Yun et al. 2019 (88)

uncommonly, patients may be clinically asymptomatic

except for an increase in serum creatinine. In this circum-
Author, Year

stance, kidney biopsy with critical evaluation of the histol-

ogy to find evidence supporting crystalline nephropathy is
quite useful. Methotrexate, the sulfa-containing medica-
tions, and protease inhibitors will be briefly reviewed.
1228 CJASN

Table 6. Drug-induced crystalline nephropathies

Preventive and Therapeutic

Culprit Medication Clinical Kidney Syndromes Histologic Findings
Strategiesa
Methotrexate Crystalluria, AKI, and CKD Crystals form annular structures IVFs before/during drug,
consisting of small needle-shaped alkalinize urine, adjust drug
crystals that stain yellow, golden, dose for kidney function; folinic
or brown on H&E stain, weak acid; glucarbidase (,60 h after
rim staining on PAS, black methotrexate); high-flux HD in
staining on JS, and positively certain circumstances
birefringent on polarization
Sulfadiazine, Crystalluria, AKI, CKD, and Interstitial fibrosis with mild Alkalinize urine, adjust dose for
sulfamethoxazole nephrolithiasis mononuclear inflammation kidney function, assure
observed in absence of sulfa euvolemia before drug
crystals within tubules or exposure
interstitium
Indinavir, atazanavir, Crystalluria, AKI, CKD, and Translucent, needle-shaped No role for urine acidification,
darunavir nephrolithiasis indinavir, atazanavir, or assure euvolemia during drug
darunavir crystals within tubules therapy; switch to different
with an associated monocytic medication
infiltrate and giant-cell reaction
Acyclovir Crystalluria, AKI, and CKD Needle-shaped crystals within Avoid rapid iv bolus, adjust drug
tubules 1/2peritubular dose for kidney function, assure
inflammation and positively euvolemia during drug therapy
birefringent on polarization
Ciprofloxacin, Crystalluria and AKI Needle-shaped crystals within Assure euvolemia during drug
levofloxacin tubules and strongly birefringent therapy and avoid alkaline
with polarization urine (if possible)
iv ascorbic acid, orlistat Crystalluria, AKI, and CKD Crystals are translucent to pale blue Ascorbic acid and orlistat: assure
(by causing enteric fan-like or sunburst shapes euvolemia during drug therapy,
hyperoxaluria), within tubules and interstitium avoid other nephrotoxins;
ethylene glycol with interstitial inflammation and fomepizole and HD for
positively birefringent on ethylene glycol
polarization
Sodium phosphate AKI and CKD Granular bluish-purplish crystal Assure euvolemia before
purgative (oral rather deposits with positive von Kossa exposure, avoid concomitant
than enema) staining and negative NSAIDs, diuretics, and RAS
birefringence on polarization blockers
Triamterene Crystalluria, AKI, CKD, and Crystals stain yellow/brown on Alkalinize urine, assure euvolemia
nephrolithiasis H&E and PAS, silver-positive on during drug therapy
JS, and strongly birefringent on
polarization
Amoxicillin Crystalluria and AKI No histologic evidence of intrarenal Assure euvolemia, adjust drug
deposits of amoxicillin crystals on dose for kidney function
biopsy
Foscarnet AKI, hematuria, proteinuria, Plates and geometric shapes in Assure euvolemia during drug
and CKD dilated capillary loops and therapy and adjust drug dose
tubular lumens associated and for kidney function
positively birefringent on
polarization

H&E, hematoxylin and eosin; PAS, periodic acid–Schiff; JS, Jones methenamine silver; IVF, intravenous fluid; iv, intravenous; HD,
hemodialysis; NSAIDs, nonsteroidal anti-inflammatory drugs; RAS, renin-angiotensin system.
a
Treatment includes drug discontinuation, intravenous fluids for hypovolemia, and supportive care including dialysis.

High-dose methotrexate causes AKI with an incidence (97–100,106). Low urinary solubility of these drugs and
ranging from 2% to 50% depending on the underlying risk their metabolites, especially in acid urine, promotes crys-
factors and AKI definition (103,104). Methotrexate and its tal precipitation within distal tubular lumens. Sulfadia-
metabolites precipitate in acid urine. Urine sediment may zine and sulfamethoxazole crystals can be visualized in
show free methotrexate crystals and crystal-containing urine sediment as free crystals or crystals within casts
casts (99,102). Crystalline cast formation in the urine sug- (97–100,106). Crystals have hourglass shapes with promi-
gests that methotrexate crystals caused AKI (99). In patients nent radial striations, are described as “sheaves of wheat,”
undergoing kidney biopsy, methotrexate crystals form and are birefringent. Crystals have not been observed in
annular structures consisting of small, needle-shaped crys- kidney tissue, but interstitial fibrosis with mononuclear
tals that stain yellow, golden, or brown on hematoxylin inflammation may reflect the effects of unseen, intrarenal
and eosin stain, whereas they are strongly birefringent crystals (105,107). As such, urine sediment examination
crystals with polarization (105). for sulfa-drug–related crystals and casts is recommended
Sulfadiazine and sulfamethoxazole are sulfa-based anti- to detect crystalline nephropathy when AKI develops
microbial agents associated with crystalline nephropathy (97,98).
CJASN 17: 1220–1233, August, 2022 AKI Associated with Common Medications, Perazella and Rosner 1229

Tubular cell A Urine

Nucleus
Cleaves
TNF-R RIPK1 Ctp-B

B
RIPK1
P
RIPK3 Phagolysosome
Urinary P rupture
crystals MLKL P
P
P RIPK-MLKL
necrosome

Interstitial
crystals C
E
TNF
Necroptosis
Dendritic cells Chemokines
and cytokines DAMPs
and macrophages
NLRP3
TLRs
F G D
IL-1E

Intrarenal Inflammation
- Leukocyte recruitment
- Inflammatory cytokines
- Vascular permeability
- Vasodilatation
- Complement activation

Figure 3. | Pathogenesis of drug-induced crystalline-related AKI. Drug crystals precipitating in the tubular lumen cause tubular obstruc-
tion (A) and induce tubular cell necroptosis by activating a number of pathways. Crystal uptake into lysosomes and phagolysomes is asso-
ciated 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 stimu-
lates 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-1b 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.

The protease inhibitors indinavir, atazanavir, and daru- concentrations develop as they traverse the tubules, which
navir also cause crystalline nephropathy. Indinavir, which enhances the likelihood for substrate supersaturation and
is no longer widely used, and atazanavir crystals have sim- crystal nucleation. Second, the nature of crystals makes
ilar appearances in the urine as needles or rectangles that them suited to precipitate and deposit within tissues, and,
form fan-shaped or starburst aggregates (102,108–111). Dar- lastly, the presence of injured cell membranes provides a
unavir crystals are more biconvex shaped and positively nidus for crystal nucleation and adhesion (113). Injured
birefringent (112). Crystals may be seen free or within casts, tubular cells combined with urinary supersaturation of the
along with leukocytes and erythrocytes. On histology, drug with crystal-forming potential provide the foundation
translucent, needle-shaped indinavir or atazanavir crystals for crystal deposition. In addition, upregulation of multiple
cluster within distal tubular lumens/collecting ducts with cellular surface molecules by injured cells creates an envi-
lymphoplasmacytic inflammation (97,100,107,108,110). Dar- ronment favorable for crystal nucleation and adhesion to
unavir crystals are also needle-shaped and birefringent on the injured cell membranes, forming a nidus upon which
histology (112). further crystal growth occurs (113).
Tubular obstruction contributes to AKI but is less impor-
Pathogenesis tant than crystal-related cytotoxicity and inflammation.
Medications, like other molecules that aggregate in a Crystals can promulgate intracellular signaling pathways
symmetrical, fixed distance as three-dimensional struc- that induce necrosis. In addition, digestion-resistant crys-
tures, can form crystals (98,100). The kidney is an ideal site tals destabilize lysosomes with subsequent release of their
for crystal deposition for several reasons. First, high drug contents such as cathepsin-B, which deregulates cell death
1230 CJASN

pathways and permits cell necrosis via autophagy and nec- Sulfadiazine- and sulfamethoxazole-associated AKI are
roptosis (114,115). Crystal-triggered cellular necrosis also considered reversible and may be prevented by avoiding
promotes release of damage-associated molecular patterns, excessive drug dosing and volume depletion. Induction of
histones, demethylated DNA and RNA, and mitochondrial high urinary flow rates and alkaline urine (pH.7.1) are
DNA into the extracellular compartment (114,115). It is useful prophylactic and therapeutic maneuvers. They also
likely that one or more of these factors engage death recep- are typically successful in promoting kidney recovery in
tors on neighboring cells and induce cell necrosis. those with AKI (97–100,106,107).
Intrarenal crystals also induce inflammation, which fur- Finally, protease-inhibitor crystalline-related kidney
ther exacerbates kidney injury (Figure 3). Crystal-induced injury is also generally reversible, although cases of CKD
inflammation and necroinflammation, which occurs in have been reported. Maintaining good hydration is impor-
response to cell necrosis, can develop through activation of tant to reduce crystalline nephropathy, although urinary
toll-like receptors by many of the factors previously acidification is not recommended (108–111,119). Dose mod-
described (114,115). After crystal-related tubular cell dam- ification is not required. Early recognition with drug dis-
age, complement activation and leukocyte invasion are pri- continuation is critical to avoid CKD from irreversible kid-
mary effectors of detrimental necroinflammation (114,115). ney fibrosis/damage (108–111,119).
Crystal-induced NLRP3 inflammasome activation and Other medications with the potential to cause crystalline-
secretion of IL-1b further contribute to intrarenal inflamma- induced AKI, such as intravenous acyclovir (rapid, bolus
tion (116). As shown in a crystalline mouse model, intrare- dose), excessive doses of oral ciprofloxacin, and other
nal crystals can also activate damage-associated molecular drugs, as well as the preventive/therapeutic measures, are
patterns that bind TLR4 and activate the NF-kB pathway, noted in Table 6.
triggering transcription and expression of several proin-
flammatory cytokines and chemokines (117). Crystals may
also promote intrarenal inflammation by inducing cell- Conclusion
surface lipid sorting and activating tyrosine protein kinase Medications are a common cause of AKI. Clinicians
Syk, which activates B cells (114,115). Inflammatory cell should be familiar with the pathogenesis and clinical-
death through pyroptosis may also develop indirectly pathologic manifestations of the three forms of drug-
through crystal-related NLRP3 inflammasome production induced AKI discussed in this brief review to adequately
(115,116). Crystal-induced necroptosis also occurs from the prevent and treat AKI associated with these agents.
injurious effects of TNF-a and other inflammatory cyto-
kines (115,116). Overall, these various crystal-related path- Disclosures
ways cause harmful inflammation and kidney injury. M.A. Perazella reports receiving honoraria from UpToDate and
serving as a scientific advisor or member of the American Journal of
Prevention and Treatment Kidney Diseases, CJASN, Clinical Nephrology, the Journal of Onco-
General principles of prevention and treatment are avail- Nephrology, Kidney360, Kidney International, and Kidney International
able to limit the complications observed with many of the Reports. M.H. Rosner reports consultancy agreements with Baxter,
drug-induced crystalline nephropathies (Table 6). Preven- receiving research funding from Kadmon and the National Insti-
tion hinges on appropriate drug dosing for level of GFR, tutes of Health, receiving honoraria from the American Society of
correcting any underlying volume depletion, achieving Nephrology and Baxter, serving as an Editor-at-Large of CJASN,
high urinary flow rates, and targeting a urine pH (when serving as a scientific advisor or member of the American Society
applicable) to prevent intratubular crystal precipitation of Nephrology, and serving on data safety monitoring boards for
(97–99). When AKI develops, treatment includes culprit Reata and Retrophin.
medication discontinuation, fluids to restore euvolemia
and enhance tubular flow rates, and avoidance of concomi- Funding
tant nephrotoxin exposure (97–99). Specific treatment con- None.
siderations for each form of crystalline nephropathy
include modification of urine pH to enhance solubility, Acknowledgments
interventions to reduce plasma and urine drug concentra- Because Dr. Mitchell H. Rosner is an Editor-at-Large of CJASN,
tions, and rarely extracorporeal therapy. he was not involved in the peer review process for this manuscript.
Prevention of methotrexate-associated AKI mandates Another editor oversaw the peer review and decision-making pro-
urine alkalinization (pH.7.10) and induction of high uri- cess for this manuscript.
nary flow rates (101,103). Folinic acid provides salvage
metabolic therapy. Options for AKI include high-flux References
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