Tubulointerstitial Injury Associated With

Chemotherapeutic Agents
Anushree C. Shirali and Mark A. Perazella
Chemotherapy holds tremendous potential in improving the survival of patients with cancer. However, the side effects of these
drugs, including those that affect the kidney, can adversely affect patient outcomes. Prompt recognition of these adverse kid-
ney effects allows early intervention that can minimize or prevent patient morbidity. In this review, we examine the nephrotoxic
potential of chemotherapy drugs. In concentrating on tubulointerstitial injury, we will review common agents that result in
acute kidney injury due to acute tubular necrosis, tubulopathies, crystal nephropathy, acute interstitial nephritis, and chronic
interstitial nephritis, and we will present preventive and management strategies.
Q 2014 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Chemotherapy, Acute kidney injury, Chronic kidney disease, Fanconi syndrome

Introduction dling marks it as a particular target for toxic drug effects.

Anticancer therapies provide oncologists with opportuni-
ties to treat their patients and favorably affect disease
progression and overall survival. Unfortunately, drug-
associated nephrotoxicity occurs commonly with some
of these agents. Clinically, patients may experience acute
kidney injury (AKI) and some of its complications,
including excessive chemotherapy drug levels due to
kidney underexcretion, increased hospitalization rates
and longer lengths of stay, and increased morbidity and
mortality. Recognizing the potential of adverse kidney
events is important for all clinicians, but in particular
for the nephrologist who is asked to evaluate and treat
new onset of kidney disease in the oncology patient.
This article will review the common clinical manifesta-
tions of chemotherapy-associated nephrotoxicity, focus-
ing on those agents that result in tubulointerstitial injury.
Risk Factors for Nephrotoxicity of
Chemotherapeutics
Drug Factors and Kidney Handling of Drugs
The propensity of chemotherapy to induce kidney dis-
ease is related to drug- and patient-specific factors
(Table 1). In fact, both factors often work in concert to en-
hance the toxicity of any particular drug regimen. Drug-
specific factors refer to the inherent properties of the
pharmacological compound. For example, the cytotoxic
effect of these drugs can affect malignant cells but also
healthy tissues, including kidney parenchymal cells.
However, in several ways, the kidney’s role in drug han-
From Section of Nephrology, Department of Internal Medicine, Yale Uni-
versity School of Medicine, New Haven, CT.
The authors report no financial conflicts of interest.
Address correspondence to Anushree C. Shirali, MD, Department of Inter-
nal Medicine, Yale University School of Medicine, PO Box 208029, New Ha-
ven, CT 06520-8029. E-mail: anushree.shirali@yale.edu
Ó 2014 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2013.06.010
Because it receives a significant percentage of cardiac out-
put, drug delivery to the kidney is highly efficient. This is
particularly true for renal tubular epithelial cells
(RTECs), which receive drug at their basolateral surface
via peritubular capillary blood flow. These agents then
enter tubular cells via uptake through organic anionic
transporters and organic cationic transporters (OCTs).1
Excretion into urine occurs when drugs are secreted
into the tubular lumen via apical efflux transporters.
Other drugs are filtered at the glomerulus and then
gain apical entry into tubular cells via endocytosis or pi-
nocytosis.2 Alteration in tubular drug transport is 1 ave-
nue by which drug toxicity may occur in certain
individuals. For example, genetic polymorphisms that
modulate the drug trafficking activity of these trans-
porters may explain patient variability in cisplatin neph-
rotoxicity.3 Once drugs are effluxed into tubular lumens
to join the glomerular filtrate, they become concentrated
as water is reabsorbed in the descending loop of Henle.
This allows a critical amount of drug to accumulate and
increases the potential for tubular cell injury. Tubular
cells in the loop of Henle and medullary collecting duct
are particularly sensitive to this because their microenvi-
ronment is relatively hypoxic due to metabolic demands.
These metabolic tasks include drug modification, for
which the kidney contains multiple enzyme systems
(including cytochrome p450) that oxidize parent com-
pounds into smaller and potentially toxic metabolites.4
In addition, these enzymatic actions generate reactive ox-
ygen species, leading to another plausible route of kidney
injury.2
Chemical characteristics of the kidney microenviron-
ment may also contribute to a specific drug’s toxic effects.
For example, methotrexate (MTX) and its downstream
metabolites require high pH for solubility. Normal hu-
man urine in a host with standard protein intake does
not naturally attain high pH. As such, MTX and related
compounds are likely to remain precipitated within the
renal tubules and cause direct cytotoxicity. Finally, it is
important to note that patients are often exposed to

56 Advances in Chronic Kidney Disease, Vol 21, No 1 (January), 2014: pp 56-63

 Tubulointerstitial Nephrotoxicity of Chemotherapy 57

multiple potential nephrotoxic agents, which increases are associated with various types of kidney injury includ-
the susceptibility to kidney injury from any particular in- ing cast nephropathy, light- and heavy-chain deposition
sult. This is especially true of patients with malignancies, disease, and amyloidosis. Lastly, metabolic abnormalities
for whom use of these agents may be necessary for such as hypercalcemia, either in isolation or as part of the
treatment or diagnostic purposes (eg, nonsteroidal anti- tumor lysis syndrome, promote afferent arteriolar vaso-
inflammatory drugs prescribed for pain or osmolar con- constriction and a functionally prerenal state.
trast agents used for imaging).
Clinical and Pathologic Spectra of
Patient Factors Tubulointerstitial Disease
Along with kidney handling and drug-specific factors,
Overview
patient-specific characteristics also modify the risk for
nephrotoxicity. Some of these characteristics may be The spectrum of kidney disease from pharmaceutical
fixed, such as age or gender. The prevalence of cancer in- agents can be grouped into the customary prerenal, intra-
creases with aging, so older persons carry a higher bur- renal, and postrenal compartments. Although most drugs
den of malignant disease. Older persons also often have claim a singular mechanism of kidney injury, other drugs
more risk factors for AKI that make them more suscepti- may affect kidney function via several pathways. Chemo-
ble to chemotherapy-associated nephrotoxicity. These therapy drugs may induce prerenal injury (eg, with the
risk factors include (1) decreased muscle mass, which re- capillary leak syndrome tied to interleukin-2 administra-
sults in reduced serum creatinine and masks reduced tion). Postrenal disease is unusual, but it has been
glomerular filtration rate (GFR); (2) decreased total described with hemorrhagic cystitis from cyclophospha-
body water, which leads to mide leading to intravesicu-
increased serum drug con- lar thrombi and bladder
CLINICAL SUMMARY
centrations; and (3) de- outlet obstruction.6 How-
creased drug binding to ever, intrinsic kidney dis-
 Nephrotoxicity is commonly associated with some
protein in states of hypoal- chemotherapy drugs. ease is the most common
buminemia, which may be site of injury with chemo-
 Risk factors for nephrotoxicity are influenced by drug and
present in the patient with therapeutic drugs and is
patient characteristics.
cancer and contributes to in- further subdivided into
creased free drug concentra-  Nephrotoxicity is clinically manifested by acute kidney glomerular, tubular, and
injury, isolated tubulopathies, and CKD.
tions in the serum. Female interstitial pathology. Glo-
sex is also associated with  In general, nephrotoxicity can be avoided or ameliorated by merular disease from che-
reductions in total body wa- ensuring that patients are volume replete and not on motherapeutic agents is not
additional agents with nephrotoxic potential.
ter and muscle mass and common, but it may present
may be prone to drug over- as thrombotic microangio-
dosing for the same reasons. pathy, particularly with anti-
Finally, with decreased kid- angiogenesis agents and
ney reserve, any patient with CKD is at higher risk of gemcitabine.7,8 Other manifestations include focal seg-
AKI, regardless of age or gender. In summary, multiple mental glomerular sclerosis with all subclasses of inter-
factors may contribute to the kidney dysfunction asso- feron and pamidronate.9,10 Because further discussion
ciated with chemotherapy in patients with malignant of these glomerular pathologies is limited by space
diseases. considerations in the current article, we will focus on
The pathologic effects of cancer or side effects from injury to the tubular and interstitial compartments
the treatments of cancer also increase the risk of because it is the most likely to be associated with present-
chemotherapy-associated nephrotoxicity. These include day oncologic drugs. Five major pathologic states and their
vomiting and diarrhea, which increase propensity for kid- clinical presentations will be discussed: acute tubular ne-
ney injury through true volume depletion. Comorbid crosis (ATN), tubulopathies, crystal nephropathy, acute in-
conditions in the cancer patient such as congestive heart terstitial nephritis (AIN), and chronic interstitial nephritis
failure (from preexisting or drug-induced cardiomyopa- (Table 2). Representative examples of the most common
thy), malignant ascites, and sepsis reduce effective drugs in each category will be highlighted in the following
intravascular volume. Cholemic nephrosis, or jaundice- text; however, all drugs are listed in Table 2.
associated AKI, may result in the cancer patient with ob-
structive jaundice, putatively via kidney hypoperfusion ATN
5
and direct tubular toxicity from bile salts. Kidney disease Severe injury to the renal tubules results in cellular death
may also develop from malignancies such as leukemia and acute tubular injury and necrosis. Depending on the
and lymphoma via direct infiltration. Dysproteinemias particular drug, patients experience reduced GFR, usually
58 Shirali and Perazella

Table 1. Patient and Drug Characteristics That Increase Risk of Table 2. Chemotherapy Drugs Associated With Kidney Syndromes
Chemotherapy-Associated Nephrotoxicity of the Tubulointerstitium
Patient-Specific Factors Acute Tubular Necrosis
 Female gender  Cisplatin . carboplatin/oxalipatin
 Age . 65 y  Pemetrexed
 Nephrotic syndrome/hypoalbuminemia  Mithramycin
 Obstructive jaundice  Streptozocin
 Acute/chronic kidney disease  Pentostatin
B Cancer-related kidney disease  Zoledronate
B Other causes of kidney disease Tubulopathies, Fanconi syndrome
 True or effective volume depletion  Cisplatin
B Decreased GFR  Ifosfamide
B Decline in urine flow rates  Streptozocin
 Metabolic perturbations Salt wasting
B Urine pH  Cisplatin
 Immune response genes  Azacitidine
 Pharmacogenetics favoring drug toxicity Syndrome of inappropriate antidiuresis
B Polymorphisms in hepatic and kidney CYP450 system,  Cyclophosphamide
kidney transporters  Vincristine
Kidney-Specific Factors Nephrogenic diabetes insipidus
 High rate of blood delivery (20-25% of cardiac output)  Cisplatin
 Biotransformation of substances to reactive oxygen species  Ifosfamide
 High metabolic rate of tubular cells Magnesium wasting
 Proximal tubular uptake of toxins  Cetuximab, panitumumab
B Apical uptake via endocytosis/pinocytosis  Cisplatin
B Basolateral transport via OAT and OCT Crystal nephropathy
Drug-Specific Factors  Methotrexate
 Prolonged drug exposure Acute interstitial nephritis
 Direct drug or metabolite cytotoxicity of the drug or metab-  Anti-CTLA-4 antibody
olite Chronic interstitial nephritis
 Drug (or other nephrotoxin) combination that enhances  Nitrosureas
nephrotoxicity  Other drugs causing AKI
 Insoluble parent drug or metabolite with intratubular crystal
precipitation Abbreviations: AKI, acute kidney injury; CTLA-4, cytotoxic T-lym-
phocyte-associated antigen-4.
Abbreviations: CYP450, cytochrome p450 system; GFR, glomerular
filtration rate; OAT, organic anion transporter; OCT, organic cation chief mechanism of cisplatin-associated kidney injury ap-
transporter. pears to be oxidative damage, which occurs when a chlo-
ride ion on the parent drug is hydrolyzed and releases
hydroxyl radicals.12 Cisplatin causes injury primarily to
with AKI, although prolonged injury or delayed recovery
may also result in CKD. Tubular sodium reabsorption may
be compromised, thus leading to urine Na1 mEq/L
greater than 20 and fractional excretion of sodium
(FeNa) . 2%. Urine sediment may reveal RTECs and
RTEC casts and/or granular casts. With prolonged injury,
oliguric AKI may result, requiring renal replacement ther-
apy. In consultation with the oncologist, the offending
agent should be discontinued and kidney function must
be closely monitored. Several chemotherapy drugs
(Table 1) are implicated in causing ATN. In the following
sections, we will concentrate on 3 chemotherapeutic
agents that the nephrologist is likely to encounter because
they often cause renal tubular injury.
Cisplatin. Cisplatin claims undisputed tumoricidal ef-
ficacy against various solid organ tumors. However, it is Figure 1. Cisplatin-associated nephrotoxicity. Cisplatin
also potent in causing dose-dependent ATN in up to 20% causes kidney injury via multiple mechanisms. Uptake into
to 30% of patients receiving platinum therapy.11 AKI is proximal tubular cells is associated with toxicity via cell sig-
usually nonoliguric, but it may be severe enough to re- naling pathways, inflammation, and increased oxidative
stress. Vascular injury also causes tubular ischemia and
quire dialysis. Cisplatin can also result in proximal tubul- acute kidney injury. OCT-2, organic cation transporter-2;
opathy, which will be discussed later. As seen in Figure 1, RTEC, renal tubular epithelial cell; TNF-a, tumor necrosis
cisplatin may cause AKI through several pathways. The factor-a.
 Tubulointerstitial Nephrotoxicity of Chemotherapy
the proximal tubule, partly because these cells uptake
drug via organic cationic transporter-2 (OCT-2).13 The
proximal tubular cells accumulate cisplatin, and intracel-
lular conversion to metabolites favors toxic injury via
several mechanisms, including oxidative stress
and proinflammatory cytokine production.12,14 Tumor
necrosis factor-a is a particularly potent inflammatory
mediator, playing a role in mediating cisplatin-induced
kidney injury through apoptosis.12 Cisplatin also acti-
vates signaling pathways, such as mitogen-activated pro-
tein kinase, and p53, which promote cell death.12 Finally,
cisplatin may also induce injury in the kidney vascula-
ture, leading to ischemic tubular cell death and AKI.
Other platinum-based agents, such as carboplatin and
oxaliplatin, are less nephrotoxic than cisplatin because
they lack chloride ions on their stem and display de-
creased OCT-2 cellular uptake.15,16 Nonetheless, in high
doses and in patients with the aforementioned risk
factors for nephrotoxicity, there is also a measurable
risk of ATN with these derivative platinum drugs.
Prevention of cisplatin nephrotoxicity is focused on
volume repletion with saline and avoidance of other
nephrotoxic agents. Other prophylactic strategies to
reduce kidney injury include the glutathione analog
amifostine and sodium thiosulfate.2 However, these ther-
apies are not well tolerated (nausea and vomiting) and
potentially reduce tumor killing. Several other agents
studied in animals have not made it into clinical practice
(nucleophilic sulfur thiols, neurotrophins, phosphonic
acid, melanocortins, and free oxygen radical scaven-
gers).2 Treatment of cisplatin-induced ATN begins with
cessation of further dosing. If electrolyte and acid-base
abnormalities are severe (hyperkalemia, metabolic acido-
sis), then a period of renal replacement therapy may be
necessary. Sodium thiosulfate and other antioxidant
drugs have been proposed as therapy for ATN with plat-
inum drugs, but the side effects of these drugs and vari-
able efficacy have limited their clinical use thus far.
Another theoretical approach to prevent cisplatin neph-
rotoxicity involves the use of substrates that would com-
pete for uptake via OCT-2 such as cimetidine, but thus far
this approach has not been studied clinically.
Ifosfamide. In producing the nephrotoxic metabolite
chloracetaldyhyde (Fig 2), ifosfamide is unique from its
parent drug, cyclophosphamide, in inducing tubular
injury. The kidney may be susceptible because the cyto-
chrome p450 enzymes that are responsible for the metabo-
lism of ifosfamide into toxic substrates may be highly
expressed in the kidney.17 In addition, basolateral uptake
of ifosfamide via the OCT-2 transporter, which does not
transport cyclophosphamide, enhances ifosfamide neph-
rotoxicity. Antagonism of the OCT-2 transporter with
a drug such as cimetidine is a potential strategy to reduce
tubular injury.2 Ifosfamide is an alkylating agent that is
used in treating several solid organ tumors as well as cer-
tain lymphomas and sarcomas. The risk of AKI with ifos-
59
Figure 2. Ifosfamide-associated nephrotoxicity. Unlike cy-
clophosphamide, methotrexate is transported into proximal
tubular cells via the OCT-2 on the basolateral membrane and
is metabolized to the tubular toxic substance chloracetalde-
hyde. AKI, acute kidney injury; ATN, acute tubular necrosis;
OCT, organic cation transporter-2.
famide is less compared with cisplatin and correlates with
cumulative lifetime drug exposure. In addition to total
drug exposure of more than 100 g/m2, previous cisplatin
use may be an independent risk factor.18 More common
than AKI, ifosfamide is associated with proximal tubular
dysfunction that may present as Fanconi syndrome (FS)
or as isolated renal tubular acidosis.19
Pemetrexed. Pemetrexed is a structural analog of the
antifolate agent MTX, which causes tubular injury via
crystal deposition (discussed later). However, data from
a recent case report suggest that pemetrexed induces di-
rect tubular injury, causing ATN.20 The risk is higher in
patients who received prior potentially nephrotoxic che-
motherapy and in those with risk factors for CKD such
diabetes and hypertension. Apical folate receptors and/
or basolateral folate carriers may transport pemetrexed
into tubular cells; thus, cytotoxicity is tied to an antifolate
effect that impairs DNA and RNA synthesis. Kidney bi-
opsies in patients with pemetrexed-associated AKI dis-
play features typical of ATN, including loss of brush
border and tubular atrophy.20
Tubulopathies
Some agents that cause ATN and AKI may also display
metabolic and water derangements. These abnormalities
reflect isolated tubular injury at distinct segments and
may occur with either reduced GFR or preserved kidney
function.
Proximal Tubule. FS is the clinical description for gener-
alized dysfunction of the proximal tubule, which is
60 Shirali and Perazella
responsible for bicarbonate, amino acid, glucose, and
phosphate reabsorption from newly filtered fluid. Thus,
the major clinical features of proximal tubulopathy in-
clude nondiabetic glucosuria, renal tubular acidosis,
and urinary phosphate wasting. Urine studies are reveal-
ing of these features, although incomplete FS will not dis-
play all of these abnormalities. In these subclinical cases,
other urinary biomarkers have been suggested for early
diagnosis, including retinol binding protein and b-2 mi-
croglobulin.21 Among chemotherapy drugs, ifosfamide
and cisplatin are most commonly seen with complete
FS, whereas imatinib use is reported to cause hypophos-
phatemia from a partial proximal tubulopathy.22 Despite
cessation of ifosfamide therapy, tubulopathy manifested
by impaired phosphate reabsorption may persist for
years in survivors of childhood malignancies.21 Although
these persistent changes may not result in serum electro-
lyte abnormalities, the effect on more subtle parameters
such as bone growth, etc, is unclear.21
Loop of Henle. In addition to ATN and FS, cisplatin may
also cause a salt-wasting nephropathy. Although much
more rare than a diagnosis of ATN or FS, in a single-
center report, 10% of patients treated with conventional
cisplatin doses developed profound volume depletion,
which was characterized by orthostatic blood pressures
changes, polyuria, and inappropriately high urine so-
dium concentrations.23 It is interesting to note that half
of the patients required continued management of kid-
ney sodium wasting for months after discontinuation of
cisplatin, indicating severe and irreversible injury in
some cases.23 The mechanism is thought to involve injury
at the loop of Henle, which impairs the kidney’s ability to
concentrate urine and leads to polyuria. Proximal tubular
injury is likely the primary mechanism behind the salt-
wasting phenomenon. The loop of Henle also par-
ticipates in paracellular magnesium transport; thus,
hypomagnesemia may accompany the salt-wasting syn-
drome with cisplatin.
Collecting Duct and Distal Tubule. The distal nephron is
the primary site for magnesium reabsorption in the
kidney. This is principally mediated by the epithelial
channel transient receptor potential M6, which depends
on epidermal growth factor receptor signaling for
activation. Hypomagnesemia due to urinary magne-
sium wasting is increasingly being described in as-
sociation with novel anti-epidermal growth factor
receptor targeted antibody therapies including cetuxi-
mab and panitumumab. Patients receiving these agents,
which are gaining favor in the treatment of metastatic
colon cancer and other malignant diseases, have an
incidence rate of hypomagnesemia that ranges between
10% and 36% in clinical trials.24,25 Fractional excretion of
magnesium in the urine exceeding 15% in the setting of
hypomagnesemia is diagnostic of kidney magnesium
wasting. Oral magnesium supplements are the first
line of treatment; however, because they have intoler-
able gastrointestinal side effects that limit patient
adherence and are not always effective, intravenous
dosing is often required. Fortunately, kidney mag-
nesium wasting resolves 4 to 6 weeks after drug
discontinuation.
Water handling at the collecting tubule is under the
control of the hormone vasopressin (or antidiuretic hor-
mone). In the kidney, vasopressin binds primarily to the
vasopressin receptor 2, initiating a G-protein-coupled
signaling cascade that results in the insertion of water-
permeable channels in the apical membrane of the collect-
ing duct. A luminal osmotic gradient allows water to
move into the cells of the collecting duct, after which it
moves across the freely permeable basolateral membrane
into the systemic circulation. Chemotherapy drugs such
as cisplatin and ifosfamide interfere with vasopressin ac-
tivation of the arginine vasopressin receptor 2, resulting
in nephrogenic diabetes insipidus.19 Clinically, patients
experience polyuria and polydipsia, and urine studies
demonstrate low specific gravity and osmolarity, indicat-
ing an inability to appropriately concentrate urine. Unless
access to free water is limited or thirst is greatly dimin-
ished, serum sodium levels are usually in the normal to
high-normal range. Severe hypernatremia can occur
when water intake is impaired. A recent systematic re-
view suggested that remission of nephrogenic diabetes
insipidus usually occurs within several days to weeks
of drug cessation.26 On the opposite spectrum to im-
paired kidney responsiveness to vasopressin, certain che-
motherapeutic agents cause a heightened vasopressin
response, which results in water intoxication and hypona-
tremia. Patients with various malignancies are already
predisposed to hyponatremia because they often suffer
from nausea/vomiting and pain, which are potent nonos-
motic stimuli for vasopressin release. Cyclophosphamide
and vincristine are among the chemotherapeutic agents
that potentiate the release and effect of vasopressin.19
Crystal Nephropathy. Some chemotherapeutic drugs are
directly cytotoxic to renal tubular cells. Other drugs medi-
ate tubular toxicity via formation of crystalline drug parti-
cles. Crystal nephropathy refers to acute and chronic
kidney injury resulting from precipitation and deposition
of crystals within the renal tubular lumen. Crystal precip-
itation related to drugs occurs either with the parent drug
or its metabolites and is influenced by several factors.
Among these factors, the principal one that increases the
risk of crystal nephropathy is volume depletion. Whether
true or effective volume depletion, clinical states that de-
crease urinary flow rates predispose to crystal precipita-
tion. CKD (particularly with GFR , 60) also increases
the risk of crystal nephropathy in 2 ways. First, with a re-
duced number of functioning nephrons, the kidney is
more susceptible to any insult, including crystal nephrop-
athy. Second, with reduced GFR, excessive drug dosing is
more likely to occur, especially when kidney impairment
is masked and goes unrecognized. Increased serum drug
 Tubulointerstitial Nephrotoxicity of Chemotherapy
levels lead to an increased filtered load and an intratubu-
lar drug burden that can cause kidney injury.
Malignancy-associated crystal nephropathy is gener-
ally associated with uric acid nephropathy, as seen in
the tumor lysis syndrome associated with high-grade
leukemias and lymphomas. However, this type of crystal
nephropathy is drug independent because any drug that
can cause rapid tumor killing and release large amounts
of uric acid can lead to deposition of uric acid crystals in
tubular lumens. However, drug-specific crystal nephrop-
athy in malignant states is specifically seen with MTX.
MTX is a drug with antimetabolite activity that stems
from its antagonism of the folate pathway. It is used in
treatment of several cancers, including several solid tu-
mors and leukemias. In addition, it is also included in
the treatment regimen against autoimmune diseases
such as rheumatoid arthritis, psoriasis, and to a lesser de-
gree systemic lupus erythematosis. The principal mecha-
nism by which MTX exhibits anticancer activity is via
inhibition of dihydrofolate reductase, a key enzyme
that is responsible for maintaining the active folate—tet-
rahydrofolate—levels that are necessary for pyrimidine
synthesis. Thus, use of MTX blocks the DNA and RNA
synthesis and rapid cell division that are characteristic
of tumor cells.
Up to 90% of MTX is cleared by the kidneys, and crys-
tallization within tubular fluid is enhanced by acidic pH.
MTX metabolizes into 2 primary derivatives, 7-hydroxy-
MTX and 2,4-diamino-N10-methylpteroic acid, which are
6- and 10-fold less soluble in the urine than MTX, respec-
tively. Because MTX is used to effectively treat various
diseases, it is administered over a wide dose range
from 20 mg/m2 to 1000-33,000 mg/m2; within this range
it has a generally safe record when combined with leuco-
vorin rescue. For treatment of malignancies, MTX deliv-
ery is through prolonged intravenous infusions. This
regimen is well tolerated in patients with normal kidney
function when care is taken to ensure volume repletion
that favors high urine flow rate and urine alkalinization.
These steps are preventive measures to avoid crystalliza-
tion because an increase in urine pH from 6.0 to 7.0 re-
sults in a 5- to 8-fold increase in the solubility of MTX
and its metabolites.27 Crystallization of these substances
is the primary etiology of MTX nephrotoxicity, although
direct tubular toxicity may also play a role.
MTX-induced kidney dysfunction is tied to high se-
rum drug and metabolite levels and usually manifests
as nonoliguric AKI. With proper preventive strategies,
the risk of AKI is estimated at 1.8% on the basis of osteo-
sarcoma trials.28 Although most cases display peak
serum creatinine concentration at 1 week postdosing,
with recovery 2 to 3 weeks later, some cases may develop
prolonged and severe AKI. In these cases, plasma MTX
concentrations may rise further and increase the risk for
systemic toxicities of MTX, which include bone marrow
suppression and neurotoxicity.
61
Preventive strategies such as leucovorin with or with-
out thymidine rescue to protect against high MTX levels
and administration of alkaline fluid to increase urine
solubility (Fig 3) are paramount in avoiding toxic drug
effects.25 However, specific treatment strategies also ex-
ist. Hemodialysis-based methods have also been used,
with high-flux dialysis displaying the greatest potency
in decreasing MTX levels.27 However, a limitation of
this method is that MTX plasma levels rebound quickly
after cessation of dialysis. The U.S. Food and Drug
Administration-approved drug Carboxypeptidase G2
(glucarpidase) is a recombinant enzyme that metabo-
lizes MTX into nontoxic derivatives. In a retrospective
trial that enrolled patients with MTX-induced nephro-
toxicity and elevated plasma MTX levels, glucarpidase
lowered levels by 98% within 15 minutes.29 More impor-
tantly, the levels remained low, and most patients did
not require additional drug dosing. The metabolites
generated by glucarpidase can cross-react with commer-
cial MTX assays; therefore, care must be taken in inter-
preting levels that are obtained with these assays.
Because leucovorin is also a substrate for glucarpidase,
it should not be dosed within 2 hours of the enzyme be-
ing dosed. At this time, there are no trials examining the
efficacy of hemodialysis vs glucarpidase in the treat-
ment of MTX toxicity complicated by AKI. Because
plasma levels rebound after high-flux hemodialysis,
glucarpidase appears to be the most efficient strategy
in achieving sustained reduction in MTX levels.
Figure 3. Prevention and treatment of methotrexate nephro-
toxicity. High-risk patients more commonly develop nephro-
toxicity from high-dose methotrexate. Preventive strategies
include intravenous fluids, urinary alkalinization, and leuco-
vorin rescue. When acute kidney injury develops and drug
levels are excessive, glucarbidase and high-flux hemodialy-
sis should be considered. HD, hemodialysis; IV, intravenous;
GFR, glomerular filtration rate.
62 Shirali and Perazella
However, at this time, the cost of this therapy remains
somewhat prohibitive.
AIN
Despite the many reports linking a wide variety of drugs
to AIN, these cases are rare with conventional chemo-
therapy drugs. A possible exception to this may be novel
biological chemotherapeutics that generally involve the
use of monoclonal antibodies to modulate anticancer
T cell immunity. For example, a single case report de-
scribed AIN associated with use of an antibody directed
against cytotoxic T-lymphocyte-associated antigen-4.30
This drug had been previously linked to drug-induced
lupus nephritis,31 but in the case of AIN, the authors
describe kidney biopsy findings that include a dense
inflammatory infiltrate, predominantly consisting of
CD81 T cells, and no glomerular pathology.30 This drug
has been linked to inflammatory disease in other organs,
including enterocolitis and thyroiditis, suggesting the
possibility of autoimmunity rather than true drug sensi-
tivity as the basis for kidney inflammation.32 However,
despite this lone report implicating cytotoxic T-lympho-
cyte-associated antigen-4 antagonism, there is not a col-
lected body of evidence at this point to suggest a strong
association between AIN and chemotherapeutic agents.
Chronic Interstitial Disease
As mentioned earlier, chemotherapeutic drugs may cause
prolonged AKI with delayed recovery, ultimately result-
ing in irreversible kidney damage and CKD. This is
most often ascribed but not limited to those drugs that
cause toxic tubular injury such as cisplatin, MTX, and ifos-
famide. Histologically, the kidney parenchyma displays
chronic changes, including tubular atrophy and general-
ized interstitial fibrosis. Glomerular scarring is also noted
in these histological sections. Such severe disease is more
likely to develop if certain drug- and patient-specific risk
factors are present. These include excessive drug levels,
concomitant use of other nephrotoxic agents, and under-
lying diseases such as diabetes mellitus and hypertension
that confer higher risk of CKD if present. Other agents
such as the nitrosureas are less likely to cause AKI, but
they lead to progressive CKD over a period of months
to years because of chronic tubulointerstitial nephritis.
The nitrosureas are alkylating agents that are the fa-
vored therapy for certain malignancies because of their
ability to cross the blood-brain barrier. They are generally
associated with dose-dependent nephrotoxicity that is clin-
ically characterized by slowly progressive CKD; however,
streptozocin has also been associated with AKI and FS.
Biopsy studies demonstrate chronic changes including
tubular atrophy, interstitial fibrosis, and glomerulosclero-
sis.33 Although all nitrosureas carry some nephrotoxic
risk, streptozocin and semustine maintain higher risk
when compared with carmustine and lomustine.34
Conclusion
Chemotherapeutic agents lead to several types of kidney
tubulointerstitial disease, including AKI from ATN, tu-
bulopathies, crystal nephropathy, and acute or chronic
tubulointerstitial nephritis. Clinically, patients may expe-
rience AKI that recovers or progresses to CKD. Isolated
acid-base or electrolyte abnormalities are also common
kidney consequences of these drugs. It is important to
note that patient- and drug-specific factors confer neph-
rotoxic risk and influence the development of these kid-
ney abnormalities. Knowledge of these factors and the
prevention and treatment of chemotherapy-associated
nephropathies is essential to the overall care of the pa-
tient with malignant disease.
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