Nephrotoxicity From Chemotherapeutic Agents: Clinical Manifestations, Pathobiology, and Prevention/Therapy

Article (PDF Available)inSeminars in Nephrology 30(6):570-81 · November 2010with194 Reads
DOI: 10.1016/j.semnephrol.2010.09.005 · Source: PubMed
Nephrotoxicity remains a vexing complication of chemotherapeutic agents. A number of kidney lesions can result from these drugs, including primarily tubular-limited dysfunction, glomerular injury with proteinuria, full-blown acute kidney injury, and long-term chronic kidney injury. In most cases, these kidney lesions develop from innate toxicity of these medications, but underlying host risk factors and the renal handling of these drugs clearly increase the likelihood of nephrotoxicity. This article reviews some of the classic nephrotoxic chemotherapeutic agents and focuses on examples of the clinical and histopathologic kidney lesions they cause as well as measures that may prevent or treat drug-induced nephrotoxicity.
Nephrotoxicity From Chemotherapeutic
Agents: Clinical Manifestations,
Pathobiology, and Prevention/Therapy
Mark A. Perazella, MD, FASN,* and Gilbert W. Moeckel, MD, PhD, FASN
Summary: Nephrotoxicity remains a vexing complication of chemotherapeutic agents. A
number of kidney lesions can result from these drugs, including primarily tubular-limited
dysfunction, glomerular injury with proteinuria, full-blown acute kidney injury, and long-term
chronic kidney injury. In most cases, these kidney lesions develop from innate toxicity of
these medications, but underlying host risk factors and the renal handling of these drugs
clearly increase the likelihood of nephrotoxicity. This article reviews some of the classic
nephrotoxic chemotherapeutic agents and focuses on examples of the clinical and his-
topathologic kidney lesions they cause as well as measures that may prevent or treat
drug-induced nephrotoxicity.
Semin Nephrol 30:570-581 © 2010 Published by Elsevier Inc.
Keywords: Chemotherapy, cancer, drugs, nephrotoxicity, cisplatin, methotrexate,
ifosfamide, pamidronate
apid advances in cancer therapy have
changed the landscape of oncology for
patients and practitioners. Patients are
deriving significant benefit with increased sur-
vival, decreased tumor progression, and in
some cases with less severe overall adverse
drug effects. Unfortunately, nephrotoxic effects
of these agents remain a significant untoward
complication, and sometimes limit effective
Clinicians ordering these drugs and
nephrologists consulting when an adverse renal
event develops should be familiar with the pa-
tient factors that increase nephrotoxic risk,
clinical and histopathologic manifestations of
renal toxicity, and prevention and treatment of
chemotherapy-induced nephrotoxicity. This ar-
ticle reviews these areas, focusing on drugs that
represent examples of the various types of kid-
ney toxicity that develop from these agents.
The nephrotoxicity of chemotherapeutic agents
is enhanced by underlying host risk factors, gen-
eral renal handling of these drugs, and innate
toxicity of the individual agent (Table 1). More
than one of these factors commonly conspires
to increase risk for nephrotoxicity. Importantly,
various forms of malignancy are associated with
risk for many of these factors. For example,
both true and effective decreases in circulating
blood volume, hepatic dysfunction and obstruc-
tive jaundice, metabolic disturbances, and nu-
merous forms of acute or chronic kidney injury
result from either direct cancer effects or other
indirect effects of the malignant process. As
many as 60% of patients manifest some form
of kidney disease.
Examples include myeloma-
associated kidney disease, renal infiltration by
tumor, secondary glomerulonephritides (ie,
membranous glomerulonephritis), urinary ob-
struction from various cancers, tumor lysis
syndrome, hypercalcemia, and other forms of
neoplastic injury. Host factors, kidney drug
handling pathways, and drug toxicity factors
are briefly reviewed later.
*Section of Nephrology, Department of Medicine, Yale University School of
Medicine, New Haven, CT.
†Department of Pathology, Yale University School of Medicine, New Haven,
Address reprint requests to Mark A. Perazella, MD, FASN, Section of Ne-
phrology, Boardman Building 114, 330 Cedar St, New Haven, CT 06520-
8029. E-mail:
0270-9295/ - see front matter
© 2010 Published by Elsevier Inc. doi:10.1016/j.semnephrol.2010.09.005
Seminars in Nephrology, Vol 30, No 6, November 2010, pp 570-581570
Host Factors
Nonmodifiable risk factors such as older age
and female sex are associated with reductions
in total body water and unrecognized lower
glomerular filtration rate (GFR) despite normal
serum creatinine levels, leading to drug over-
dosage. The elderly, often afflicted by cancer,
have increased propensity to vasoconstriction
from excessive angiotensin-II and endothelin
and higher levels of oxidatively modified bi-
Vomiting, diarrhea, and diuretic use lead to
true volume depletion, while congestive heart
failure, ascites, and sepsis promote effective vol-
ume depletion in cancer patients receiving che-
motherapy and increase renal vulnerability to var-
ious agents. In addition, malignancy-induced
nephrotic syndrome and hepatic dysfunction in-
crease risk through multiple mechanisms that in-
clude altered renal perfusion from reduced effec-
tive circulating blood volume, hypoalbuminemia
with increased free circulating drug, and unrec-
ognized renal impairment.
obstructive jaundice also enhances toxicity to
certain drugs through decreased renal blood
flow and direct effects of bile salts on tubular
Renal hypoperfusion and prerenal
azotemia increase nephrotoxicity of drugs ex-
creted primarily by the kidney, in those reab-
sorbed in the proximal tubule, and in those that
are insoluble in the urine, where crystal precip-
itation occurs within distal tubular lumens with
sluggish flow.
Metabolic disturbances resulting from cer-
tain tumors also increase renal vulnerability to
certain drugs and potential toxins. Severe hy-
percalcemia, which often complicates my-
eloma and lung cancer, induces afferent arterio-
lar vasoconstriction and renal sodium/water
wasting, leading to prerenal physiology, which
enhances nephrotoxic drug injury. Systemic
metabolic acidosis may decrease urine pH and
increase intratubular crystal deposition with
drugs such as methotrexate and its metabolites,
which are insoluble in a low pH environment.
Hyperuricemia and acute tumor lysis exacer-
bate renal injury further.
Underlying acute kidney injury (AKI) and
chronic kidney disease (CKD) are important
risk factors for increasing vulnerability to neph-
Table 1. Risk Factors for Chemotherapy-
Induced Renal Toxicity
Host factors
Older age and female sex
Nephrotic syndrome, cirrhosis, obstructive
Acute or chronic kidney disease
True or effective circulating blood volume
Diminished GFR
Increased proximal tubular toxin
Sluggish distal tubular urine flow rates
Metabolic disturbances
Hypokalemia, hypomagnesemia,
Alkaline or acid urine pH
Immune response genes
Increased allergic reactions to drugs
Pharmacogenetics favoring drug/toxin
Gene mutations in hepatic and renal
cytochrome P450 enzyme systems
Gene mutations in transport proteins
and renal transporters
Renal drug handling
High blood (and drug) delivery rate to the
Relatively hypoxic renal environment
Increased drug/toxin concentration in
renal medulla and interstitium
Biotransformation of substances to reactive
oxygen species, causing oxidative stress
High metabolic rate of tubular cells in the
loop of Henle
Proximal tubular uptake of toxins
Apical tubular uptake via endocytosis or
other pathway
Basolateral tubular transport via organic
anion transporter and organic cation
transporter pathways
Innate drug toxicity
High-dose drug/toxin exposure and
prolonged course of therapy
Insoluble drug or metabolites form crystals
within the intratubular lumens
Potent direct nephrotoxic effects of the
drug or toxin
Drug combinations enhance nephrotoxicity
Nonsteroidal anti-inflammatory drugs,
aminoglycosides, radiocontrast
Nephrotoxicity from chemotherapeutic agents 571
rotoxic injury.
Excessive drug dosing, expo-
sure of a reduced number of functioning
nephrons to toxins, development of ischemia-pre-
conditioned tubular cells, and more robust renal
oxidative injury response to toxins are all contrib-
utors in these 2 settings.
The underlying genetic makeup of the host
also can enhance renal vulnerability to potential
The drug or its metabolite
form adducts that modify their physical struc-
ture, making them more immunogenic. A
heightened allergic response owing to differ-
ences in innate host immune response genes
can predispose certain patients to development
of drug-induced acute interstitial nephritis.
Pharmacogenetics also may explain the hetero-
geneous response of patients to drugs as it
relates to efficacy and toxicity. Renal cyto-
chrome P450 enzymes importantly participate
in drug metabolism
and gene polymor-
phisms favoring reduced metabolism could in-
crease nephrotoxic risk as well. Polymorphisms
of genes encoding proteins involved in the me-
tabolism and subsequent renal elimination of
drugs have been described and are correlated
with various levels of drug sensitivity. Loss-of-
function mutations in apical secretory trans-
porters and mutations in kinases that regulate
drug carrier proteins can impair drug elimina-
tion and promote nephrotoxicity by increasing
intracellular toxin concentrations.
Renal Drug Handling
The mechanism by which the kidney metabo-
lizes and excretes various drugs also may in-
crease nephrotoxicity. Significant renal expo-
sure occurs owing to the high rate of drug
delivery to the kidney, a result of the high blood
flow to the kidney, which approaches 25% of
cardiac output. Many renal cells, particularly
those in the loop of Henle and medullary col-
lecting duct, exist in a relatively hypoxic envi-
ronment owing to the high metabolic rates re-
quired by active transport processes and
decreased blood flow to inner-medullary re-
gions. This excess cellular workload and hy-
poxic environment promotes increased sensi-
tivity to injury when exposure to potentially
nephrotoxic substances occurs.
High con-
centration of parent compounds and their me-
tabolites accumulate in the renal medullary
cells and interstitium through the enormous
concentrating ability of the kidney.
creased tissue concentration of these drugs pro-
motes injury through both direct toxicity and
ischemic damage.
Biotransformation of drugs by multiple renal
enzyme systems, including cytochrome P450
and flavin-containing monooxygenases, favors
the formation of toxic metabolites and reactive
oxygen species.
The presence of these by-
products of metabolism tilts the balance in
favor of oxidative stress, which outstrips nat-
ural antioxidants and increases renal injury via
nucleic acid alkylation or oxidation, protein
damage, lipid peroxidation, and DNA strand
Enhanced toxicity in proximal tubular cells
occurs as a result of the extensive cellular up-
take of drugs by basolateral transport systems.
Proximal tubular cell toxin exposure occurs via
basolateral delivery of exogenous organic ions
by peritubular capillaries.
Drug delivery via
peritubular capillaries is followed by uptake
into proximal tubular cells via a family of trans-
porters, including human organic anion and
cation transporters.
Loss-of-function muta-
tions in and competition for apical secretory
which reduces toxin efflux from
cell into urine, may promote accumulation of
toxic substances within the proximal tubular
cell and cause cellular injury via apoptosis or
necrosis. This extensive trafficking of sub-
stances increases renal tubular exposure and
risk for increased concentration of toxin when
other risk factors supervene.
Innate Drug Toxicity
The underlying characteristics of the offending
drug also play an important role in the devel-
opment of nephrotoxicity. Prolonged therapy
at high doses with toxic drugs enhances renal
injury based on excessive renal exposure, even
in the absence of other risks. Methotrexate and
its metabolites are insoluble in human urine and
may cause renal injury through tubular obstruc-
tion or direct toxicity. Drug combinations also
increase the risk of nephrotoxicity. Exposure to
drugs such as aminoglycosides, nonsteroidal
anti-inflammatory drugs, radiocontrast, and other
572 M.A. Perazella and G.W. Moeckel
nephrotoxins are examples of enhanced nephro-
toxic risk when cancer chemotherapeutic agents
are administered concurrently.
A unique and newly recognized form of
nephrotoxicity has been described with anti-
angiogenesis therapy.
Vascular endothelial
growth factor, produced by podocytes, is re-
quired to maintain normal fenestrated endothe-
lial cell function and is particularly important
for normal functioning of the glomerular base-
ment membrane.
Reduction in vascular endo-
thelial growth factor or its effects by the various
anti-angiogenic drugs leads to loss of the
healthy fenestrated endothelial phenotype and
promotes microvascular injury and thrombotic
microangiopathy, causing proteinuria and kid-
ney disease. Reduced nephrin expression in the
slit diaphragms from these drugs also may con-
tribute further to proteinuria.
Unfortunately, several untoward consequences
may develop from kidney injury caused by
these drugs. Acute effects include increased
morbidity such as infectious complications,
prolonged length of hospital stays, increased
costs, and higher mortality rates. These acute
complications are caused in part by the adverse
effects of AKI itself as well as the extrarenal
toxicities of high drug levels from underex-
creted drugs in the setting of reduced GFR.
These include bone marrow suppression;
breakdown of skin and other mucosal barriers;
volume depletion with hypotension from vom-
iting, diarrhea, and other insensible losses; and
other end-organ dysfunction. Also, the occur-
rence of AKI very often leads to loss of tumor
therapy owing to withholding, discontinuing,
or underdosing of chemotherapeutic agents
while renal function is abnormal. Removal with
dialysis or continuous renal replacement ther-
apy may reduce drug efficacy further. This ulti-
mately may impair effective tumor therapy and
ultimate death from progressive cancer.
A two-fold increase in mortality was noted in
critically ill patients with cancer who devel-
oped a 10% increase in serum creatinine level.
Mortality rates of hospitalized patients with a
malignancy and AKI in the setting of multi-
organ dysfunction range from 72% to 85%,
higher than those without cancer.
Many of
these patients likely develop severe AKI that
requires acute dialysis or continuous renal re-
placement therapy.
Patients who survive their malignancy may
very well be left with some level of CKD or
even end-stage renal disease requiring long-
term dialysis therapy or renal transplantation.
Both CKD and end-stage renal disease are asso-
ciated with increased morbidity (anemia, renal
osteodystrophy, cardiovascular disease, malnu-
trition, and others) and mortality. Hypertension
often accompanies kidney disease, increasing
risk for other cardiovascular complications
above and beyond that associated with CKD
alone. Metabolic complications such as hypoka-
lemia, hypophosphatemia, metabolic acidosis,
and hypomagnesemia may complicate therapy
and cause assorted chronic conditions such as
osteomalacia, osteoporosis, increased risk for
cardiac arrhythmias, muscle cramping, and
chronic inflammation. Metabolic disturbances
can be permanent, depending on agent and
dose administered.
It is critical for clinicians to recognize the
early symptoms and signs of nephrotoxicity
in patients receiving culprit chemotherapeutic
agents. Unfortunately, small changes in renal
function (0.3-mg/dL increase in serum creati-
nine level) that meet the definition of AKI often
are clinically asymptomatic. Thus, those provid-
ing care to these patients must monitor serum
chemistries and examine the urine with urinal-
ysis and microscopy to recognize renal dysfunc-
tion as early as possible. Because it is not pos-
sible to cover all of the clinical presentations,
we will review those that are of most interest or
represent newer nephrotoxins. Four major clin-
ical presentations will be discussed: tubulopa-
thies, AKI, nephritic/nephrotic syndrome, and
chronic kidney disease (Table 2).
Several agents are capable of causing isolated
tubular injury. Many cause both tubular injury
Nephrotoxicity from chemotherapeutic agents 573
and a reduction in GFR (either AKI or CKD),
especially with higher doses. Drugs that cause
injury to one or more tubular segments include
cisplatin, ifosfamide, azacitidine, and diazi-
quone, all of which are associated with Fanconi
syndrome (FS).
Cetuximab causes isolated re-
nal magnesium wasting whereas imatinib and
gefitinib promote renal phosphate wasting and
hypophosphatemia as the result of a partial Fan-
coni syndrome.
Drugs such as vincristine and
cyclophosphamide enhance release of antidi-
uretic hormone, increasing risk of hyponatre-
mia from inappropriate water retention. Only
ifosfamide and cetuximab are discussed.
Ifosfamide is well known to cause proximal
tubular injury and FS, as well as nephrogenic
diabetes insipidus (NDI), and, less commonly,
AKI. The metabolite chloracetaldehyde is thought
to cause tubular injury. Risk factors for renal
injury include previous exposure to cisplatin,
underlying CKD, and cumulative dose exceed-
ing 90 g/m
Moderate to high risk of toxicity
occurs with doses in excess of 100 g/m
These various tubulopathies can be perma-
nent in 25% (moderate to severe) to 44%
(mild) of patients.
FS, which occurs in up
to 25% of patients, is characterized by urinary
wasting of potassium, phosphate, bicarbon-
ate (type 2 renal tubular acidosis), uric acid,
and glucose. Symptoms reflecting these elec-
trolyte, divalent, and acid-base disturbances
may develop, however, the syndrome most
often comes to attention from abnormal se-
rum (hypokalemic metabolic acidosis, hy-
pophosphatemia) and urine (glucosuria, phos-
phaturia) test results.
Over time, chronic
effects of these abnormalities include osteoma-
lacia, osteoporosis, hypokalemic nephropathy,
and enhanced cardiac arrhythmias in certain
patients. NDI is manifested as polyuria unre-
sponsive to vasopressin. Hypokalemia can ex-
acerbate this problem further through direct
tubular effects.
The histopathologic features of FS induced
by ifosfamide are similar to those found with
other causes of this entity. By light microscopy,
loss of proximal tubule brush-border mem-
brane and mild acute tubular injury is often the
only detectable lesion. Examination of ultra-
structural changes by transmission electron mi-
croscopy reveals abnormal mitochondrial dila-
tion with absent cristae (Fig. 1A). Abnormal
mitochondrial function leads to impairment of
sodium-potassium adenosine triphosphatase
pump that maintains the sodium gradient
across the proximal tubular epithelium. The
ifosfamide metabolite chloracetaldehyde has
been shown to impair proximal tubular trans-
port through a similar mechanism.
Table 2. Categories of Chemotherapy-
Induced Renal Toxicity
Cisplatin, ifosfamide, azacitadine,
Diaziquone, imatinib, gefitinib
Salt wasting
Cisplatin, azacitidine
Magnesium wasting
Cisplatin, cetuximab, panitumumab
Cisplatin, ifosfamide
Syndrome of inappropriate antidiuretic
Cyclophosphamide, vincristine
Prerenal kidney injury (capillary leak
Interleukin-2, denileukin diftitox
Acute tubular necrosis
Platinums, zoledronate, ifosfamide,
Pentostatin, imatinib, diaziquone
Crystal nephropathy
Thrombotic microangiopathy
Mitomycin C, gemcitabine
Nephritic/nephrotic syndromes
Thrombotic microangiopathy
Anti-angiogenesis agents, mitomycin C,
Minimal change disease
Interferon, pamidronate
Interferon, pamidronate
Chronic interstitial nephritis
Nitrosureas, cisplatin, MTX
574 M.A. Perazella and G.W. Moeckel
Cetuximab, a monoclonal antibody against
the epidermal growth factor (EGF) receptor, is
a new anticancer agent used for metastatic
colorectal cancer and other malignancies.
nary magnesium wasting is its major adverse
renal effect. The EGF receptor is expressed in
renal epithelia, where EGF binding activates the
channel TRPM6 (transient receptor po-
tential cation channel, subfamily M, member 6)
in the apical membrane of the distal convoluted
tubule, ultimately promoting Mg
tion. Not surprisingly, EGF-receptor blockade
with cetuximab causes magnesuria, potentially
leading to severe hypomagnesemia in approxi-
mately 10% to 15% of patients. Diagnosis is
clinched by showing an increased fractional
excretion of magnesium (15% in the setting of
hypomagnesemia). Panitumumab, another EGF-
receptor antibody, also is associated with mag-
nesuria because 36% of treated patients in a
phase III trial developed hypomagnesemia, of
which 3% manifested severe symptomatic hy-
Oral and intravenous magne-
sium supplementation often are required to re-
duce cramping, arrhythmias, and other related
electrolyte disturbances (hypokalemia).
Unfortunately, chemotherapeutic agents are a
common cause of AKI (Table 2). The traditional
classification of AKI can be applied to these drugs
because they cause injury in all renal compart-
ments—prerenal, intrinsic (parenchymal), and
Most commonly, AKI results from
acute tubular injury (ATI) that occurs in a dose-
related fashion from several drugs. Less com-
monly, prerenal AKI results from drugs such as
interleukin-2 and denileukin, which cause a cap-
illary leak syndrome. Other forms of parenchymal
renal injury associated with AKI occur with these
drugs including thrombotic microangiopathy and
Figure 1. (A) Ultrastructural findings of ifosfamide-induced proximal tubule injury. There is mild apical blebbing of the
brush-border membrane. The cytoplasm shows small vacuoles and the mitochondria are dilated with distorted cristae
(magnification, 12,000). (B) ATI seen in a case of cisplatin toxicity. The proximal tubule shows significant luminal
dilation with flattened epithelium and extensive nuclear drop-out. Short stretches of the basement membrane are
denuded (periodic acid–Schiff, 200). (C) Transmission electron micrograph of a glomerular capillary loop with
intraluminal large fibrin thrombus in a case of mitomycin C–induced thrombotic microangiopathy. There is endothelial
swelling and numerous fibrin tactoids are present within the capillary lumen (magnification, 8,000). (D) Glomerulus
with collapsing glomerulopathy in a patient treated with pamidronate. The glomerular capillary lumen are markedly
contracted, podocytes are enlarged, and there is early tubular atrophy adjacent to glomeruli (Jones, 200).
Nephrotoxicity from chemotherapeutic agents 575
crystal nephropathy. We focus on 3 example
drugs in this section— cisplatin, methotrexate,
and mitomycin C.
Acute Tubular Injury
Cisplatin is the classic nephrotoxin of the che-
motherapeutic drug class. Its efficacy as an an-
ticancer agent, especially for solid tumors, is
almost matched by its nephrotoxicity.
noted, cisplatin can cause several forms of tu-
bular injury with FS, sodium, and magnesium
wasting, and NDI causing polyuria. However,
AKI complicates therapy as the drug exposure
increases; one third of patients develop this
complication after one dose and the risk of AKI
increases with a higher cumulative dose. Prox-
imal tubular injury is in part caused by the
pathway of renal excretion of cisplatin. Entry of
drug from the peritubular capillaries into the
cell occurs via the basolateral organic cation
transporter. With escalating drug dose, high
cellular drug concentrations may induce cellu-
lar injury via multiple mechanisms that are dis-
cussed later. The clinician should be aware of
these toxicities when administering cisplatin to
patients, especially in those with risk factors for
increased nephrotoxicity (kidney disease, vol-
ume depletion, hypomagnesemia). In addition to
monitoring serum creatinine levels within 3 to 7
days after therapy, serum magnesium concen-
trations as well as urine studies to examine for
tubular injury (FS, sodium wasting, NDI) should
be undertaken.
Examination of the urine
sediment reveals renal tubular epithelial cells/
casts and/or granular casts. In those developing
ATI, the drug should be discontinued at least
temporarily. Other platinum agents such as car-
boplatin, oxaliplatin, and nedaplatin are less
nephrotoxic than cisplatin, but are not risk
free, particularly in patients with risk factors
and a high cumulative dose.
Cisplatin causes predominantly proximal tu-
bular injury, the glomerulus usually is spared.
Histologic changes are seen mostly in the pars
convoluta and pars recta of the proximal tubule
and consist of ATI with desquamation of tubu-
lar epithelial cells (Fig. 1B). Mitochondrial
swelling and nuclear pallor also have been de-
scribed in the distal nephron. Interstitial nephri-
tis is absent in most cases.
Conversion of cisplatin to toxic molecules is
an important step in the induction of nephro-
Cellular accumulation of cisplatin is
associated with the formation of reactive thiol
compounds and monohydroxyl complexes that
are highly toxic to the proximal tubule cell.
Toxic injury is mediated through a variety of
mechanisms including oxidative stress, reactive
nitrogen species, and induction of pro-apop-
totic and inflammatory pathways.
Reactive oxygen species directly affect pro-
tein synthesis and structure, DNA synthesis,
and cell repair mechanisms.
They also cause
direct mitochondrial dysfunction.
treated with cisplatin have higher concentra-
tions of peroxynitrite and nitric oxide.
initrite causes changes in protein structure and
function, lipid peroxidation, and reduction in
cell defense mechanisms.
Cisplatin activates the initiator caspase 1,
which leads to activation of the effector caspase
3 and subsequently to the induction of apopto-
sis. Cisplatin-induced ATI is reduced in caspase
1– deficient mice.
Cisplatin further initiates
increases in cytokines such as tumor necrosis
), transcribing growth factor-
and monocyte chemoattractant protein-1. TNF-
has a central role in inducing cisplatin-mediated
cell injury by inducing apoptosis, reactive oxy-
gen species, and activation of multiple cyto-
kines in the kidney. TNF-
inhibitors ameliorate
cisplatin-induced nephrotoxicity by 50% and
reduce cisplatin-induced structural damage.
null mice are protected against cisplatin-
induced renal injury.
Crystal Nephropathy
Methotrexate (MTX), an antifolate drug, is an
effective antineoplastic agent when adminis-
tered in a high dose (1 g/m
icity occurs primarily owing to precipitation of
parent drug and metabolites within tubular lu-
mens, a phenomenon known as crystal ne-
True or effective volume deple-
tion and acidic urine are 2 major risk factors for
AKI. Direct tubular toxicity also may contribute
to kidney injury. The overall incidence rate of AKI
is approximately 1.8% (range, 0%-12%), and, in
general, renal injury is reversible. Initially, an
asymptomatic serum creatinine increase develops
576 M.A. Perazella and G.W. Moeckel
with nonoliguria followed by more severe AKI.
Early on, urine microscopy often shows renal
tubular epithelial cells and/or casts. Rarely, drug
crystals are visible in the urine (if acidic), but may
not be present in an alkaline pH. Excessive MTX
levels and systemic end organ toxicity often fol-
lows prolonged AKI.
In addition to crystal precipitation, MTX has
been shown to induce formation of oxygen
radicals with subsequent cellular injury, associ-
ated with decreased adenosine deaminase activ-
Moreover, a recent study showed that
drug– drug interactions may play an important
role in high-dose MTX–induced AKI.
The in-
vestigators concluded that interaction between
high-dose MTX and piperacillin-tazobactam re-
duced renal clearance of MTX, leading to AKI.
Another mechanism of methotrexate-mediated
nephrotoxicity is through hyperhomocysteinemia,
seen in patients with deficient folate metabo-
lism. A recent study using methylenetetrahydro-
folate reductase null mice with hyperhomocystei-
nemia showed significant impairment of renal
function after MTX treatment.
These results sug-
gest that pharmacogenetic analysis of polymor-
phisms in folate-dependent enzymes may be use-
ful in optimizing MTX therapy.
Thrombotic Microangiopathy
Yet another form of AKI, thrombotic microan-
giopathy (TMA), occurs with the antitumor an-
tibiotic mitomycin C.
As with other drugs, a
higher cumulative dose (60 mg) appears to
increase the risk for TMA. In general, approxi-
mately 10% of patients develop adverse renal
effects after 5 to 12 months of mitomycin C
therapy. Although TMA may be renal-limited, hy-
pertension and a microangiopathic hemolytic
anemia with thrombocytopenia also occurs. He-
maturia and proteinuria along with AKI are com-
mon and neurologic abnormalities, skin rash, and
noncardiogenic pulmonary edema may occur.
Thrombotic microangiopathy (Fig. 1C) is
characterized by vascular thrombi located in
the preglomerular arterioles or associated with
glomerular lesions such as intracapillary fibrin
thrombi, mesangiolysis, and double contour of
glomerular basement membranes enclosing
subendothelial electron-lucent flocculent mate-
rial. Vascular thrombi may be associated with
endothelial swelling and denudation of the vas-
cular basement membrane. Besides the typical
findings of TMA, nuclear atypia in glomeruli
and tubular cells have been reported in mito-
mycin toxicity.
In a rat model of unilateral
perfusion with mitomycin, cortical necrosis,
and nuclear atypia, manifested by bizarre large
nuclei was noted in tubuli. These observations
support a direct toxic effect of mitomycin, or
one of its metabolites, on kidney cells.
Nephritic/Nephrotic Syndrome
Presentation with hematuria and proteinuria or
isolated proteinuria without AKI can occur
with certain chemotherapeutic agents (Table
2). In some cases, these renal manifestations
may precede the development of AKI. The anti-
angiogenesis drug class has brought excitement
to the cancer therapeutics, but interesting re-
nal-related complications such as hypertension,
glomerular endotheliosis, TMA, and a variety of
other renal lesions have been described. These
drugs are covered in other articles in this onco-
nephrology issue of Seminars in Nephrology
(see article by Eremina and Quaggin, p. 582).
We focus on 2 drugs that cause glomerular
pathology: interferon and pamidronate.
Immune modulators such as interferon-alfa,
interferon-beta, and interferon-
are associated
with proteinuria that often is mild and revers-
ible (up to 15%), but can be more severe with
nephrotic-range proteinuria.
Rarely, AKI may
complicate therapy with these drugs within the
first few weeks of administration. In general,
the renal lesion is reversible, but persists in
some patients even after drug discontinuation.
Renal injury by interferon is detected most often
by observing dipstick proteinuria. An increase of
serum creatinine level also signals kidney disease.
In addition to a number of glomerular diseases,
TMA, ATI, and interstitial nephritis also have been
described with interferon therapy.
Interferon-alfa treatment for hematopoietic
malignancies such as chronic myeloid leukemia
has been associated with a variety of lesions
including membranoproliferative glomerulone-
phritis, membranous glomerulopathy, and focal
segmental glomerulosclerosis (FSGS). The un-
derlying mechanisms that lead to renal injury are
uncertain but may include autoantibody-mediated
Nephrotoxicity from chemotherapeutic agents 577
immune complex deposition or cytokine-medi-
ated podocyte and endothelial cell injury. In a
recent case report describing a proliferative glo-
merulonephritis after interferon-alfa treatment,
the investigators showed immune sensitization by
a positive indirect Coombs test. They took this as
indirect proof that an idiosyncratic type of sensi-
tivity reaction may have initiated the immune
complex formation and subsequent deposition in
the glomeruli.
The bisphosphonate pamidronate is used to
correct hypercalcemia and for antitumor effects
in various forms of metastatic bone cancer.
High-grade proteinuria and AKI in patients re-
ceiving high intravenous drug doses (90-180
mg) at frequent intervals (biweekly to monthly)
was noted.
The most frequent pathologic
lesion is collapsing FSGS (Fig. 1D), although
less aggressive patterns of podocyte injury, in-
cluding minimal change disease and noncol-
lapsing FSGS, may be seen. In many cases, ne-
phrotic syndrome associated with pamidronate
is at least partially reversible after discontinua-
tion of the offending agent. Pamidronate also
has been associated rarely with diseases of the
tubules and interstitium, as noted with agents
that cause toxic nephropathy.
One mechanism associated with pamidr-
onate-induced FSGS is podocyte apoptosis.
assumption is supported by the observations of
increased mitochondrial number and variation in
mitochondrial size and shape that have been de-
scribed in podocytes and in tubular epithelium of
pamidronate-treated patients.
Concomitant tu-
bulointerstitial lesions show variable preva-
lence in pamidronate-induced FSGS. Even in the
absence of glomerular lesions by light micros-
copy significant tubular epithelial changes may
be present in patients with pamidronate-associ-
ated AKI.
Experimental animal studies have
shown a higher total rate of renal clearance of
pamidronate, exceeding the GFR, indicating ac-
tive tubular secretion.
In an animal model pam-
idronate increased urinary marker levels of tubu-
lar injury.
These findings indicate a tubulotoxic
component of pamidronate-induced injury.
It recently has been recognized that AKI may be
associated with irreversible renal injury and
CKD. This paradigm also applies to some of the
commonly used chemotherapeutic agents.
Both cisplatin and ifosfamide are described to
cause CKD after chronic exposure. Not surpris-
ingly, higher cumulative drug dose, combined
treatment with other nephrotoxins, and host
risk factors (diabetes mellitus, hypertension,
pre-existing kidney disease) are associated with
enhanced CKD. It is likely that AKI from ATI,
TMA, or other glomerular lesions lead to inter-
stitial fibrosis and glomerulosclerosis, which
follows a course of CKD.
The nitrosureas are alkylating agents that
cause slow, progressive CKD over a period of 3
to 5 years.
Streptozotocin and semustine are
the most nephrotoxic, with more than three
quarters of exposed patients developing kidney
injury, particularly with high cumulative doses
(1.4 g/m
). Carmustine and lomustine are less
nephrotoxic, causing kidney disease in approx-
imately 10% of exposed patients. Although all
of the nitrosureas cause slowly progressive loss
of kidney function, streptozotocin also causes
AKI. In addition to kidney injury characterized
by an asymptomatic increase in serum creati-
nine level, tubular insufficiency can accompany
nitrosurea therapy resulting in clinically evident
FS. Chronic tubulointerstitial nephritis, tubular
atrophy, and glomerulosclerosis underlie the
CKD, which often continues despite discontin-
uation of the drug.
In the majority of patients receiving at least 6
courses of nitrosourea, irreversible and chroni-
cally progressive renal damage occur. Kidney
biopsies from 7 of 18 patients who received a
minimum of six courses or more showed tubu-
lar atrophy, interstitial fibrosis, and glomerulo-
sclerosis (see Fig. 2A and B).
and chlorozotocin are structurally related anti-
cancer agents with variable severity in regard to
renal injury. In an animal study, a single high
dose of chlorozotocin resulted in acute injury of
the proximal tubule, followed by severe papil-
lary necrosis at a later time point. Similarly,
1-3-1-nitrosourea caused mild tubular injury ini-
tially, whereas extensive papillary collecting
duct necrosis was noticed 2 to 3 weeks after a
single high-dose application.
The result is a
slowly progressive nephropathy with karyo-
megaly in collecting duct cells after 4 weeks.
578 M.A. Perazella and G.W. Moeckel
An obvious preventive approach is to dose
drugs correctly for the underlying level of kid-
ney function. Most dosing data are based on
creatinine clearance (24-hour collection and
Cockcroft-Gault), but the Modified Diet in Re-
nal Disease estimating equation provides similar
However, it is critical to recognize
that these formulas have several limitations that
make them inaccurate. Examples include AKI,
non–steady-state kidney function, extremes of
muscle mass, and other factors. Another pre-
ventive strategy is to avoid or limit exposure to
other known nephrotoxins such as nonsteroi-
dal anti-inflammatory drugs, radiocontrast, and
aminoglycosides. Correction of urinary obstruc-
tion before drug exposure is logical.
Correction of hypovolemia with intravenous
fluids is important, and induction of high uri-
nary flow rates with various fluids will reduce
nephrotoxicity. Specific examples include uri-
nary alkalinization with isotonic sodium bicar-
bonate for MTX (reduces intratubular crystal
formation) and either intravenous isotonic or
hypertonic saline for cisplatin, which stabilizes
the molecule and reduces evolution of the re-
active aquated platinum species.
Specific antidotes garner some benefit in re-
ducing nephrotoxicity. Sodium thiosulfate and
amifostine may reduce adverse kidney effects
from cisplatin, sodium thiosulfate by acting as a
competitive analog for aquated platinum mole-
cules and amifostine through its effects as a
glutathione analog.
Both are limited by nau-
sea/vomiting and hypotension. Leucovorin res-
cue and glucarbidase (not yet approved by the
Food and Drug Administration) are useful for
MTX nephrotoxicity. Leucovorin is used within
24 to 36 hours of high-dose MTX therapy to
prevent normal cells from suffering injury.
Glucarbidase, which cleaves MTX to noncyto-
toxic metabolites, is used (compassionate basis)
when MTX levels are toxic and the risk for
systemic toxicity is significant.
Several antioxi-
dants (n-acetylcysteine, glutathione, glutamine,
vitamin C or E) show utility in various animal
models of chemotherapy-induced kidney injury
and may have a role in human beings, but def-
inite efficacy is lacking. A number of agents
targeting cisplatin metabolism, intracellular sig-
naling pathways, and inflammation are under
active investigation in animals.
Removal of drug in the setting of toxicity and
overdosage from associated AKI is somewhat
limited with current technology. Hemodialysis
with high-flux membranes clears the plasma of
MTX (76%), but is associated with immediate
postdialysis plasma rebound.
Plasmapheresis is
used with varied (and somewhat limited) suc-
cess for drug-induced TMA.
Kidney disease after chemotherapeutic drug
regimens remains a significant problem in the
management of cancer patients. Although re-
cent advances have been made to reduce the
Figure 2. (A and B) Extensive interstitial fibrosis and tubular atrophy in a patient treated with nitrosurea. The
Trichrome stain accentuates the increased interstitial matrix formation (Trichrome, 40). Several glomeruli show global
or segmental sclerosis in the same patient. The glomerular capillary lumens are solidified and there is decreased
cellularity in the areas of scarring (hematoxylin-eosin, 100).
Nephrotoxicity from chemotherapeutic agents 579
incidence of drug toxicity, many enigmatic dif-
ficulties still remain. With improved under-
standing of the molecular mechanisms that lead
to toxic injury by chemotherapeutics, a number
of toxic reactions will be avoided in the future.
Molecular profiling that indicates a patient’s
predisposition to toxic injury will allow prese-
lecting patients to a personalized drug regimen
for treatment. Finally, the development of drugs
targeting selective steps in tumor progression
will decrease the degree and incidence of toxic
injury to the kidney.
1. Sahni V, Choudhury D, Ahmed A. Chemotherapy-
associated renal dysfunction. Nat Rev Nephrol. 2009;
2. Finkel KW, Foringer JR. Renal disease in patients with
cancer. Nat Clin Pract Nephrol. 2007;3:669-78.
3. Lamiere NH, Flombaum CD, Moreau D, Ronco C.
Acute renal failure in cancer patients. Ann Med. 2005;
4. Kintzel PE. Anticancer drug-induced kidney disor-
ders. Drug Saf. 2001;24:19-38.
5. de Jonge MJA, Verweij J. Renal toxicities of chemo-
therapy. Semin Oncol. 2006;33:68-73.
6. Humphreys BD, Soiffer RJ, Magee CC. Renal failure
associated with cancer and its treatment: an update.
J Am Soc Nephrol. 2005;16:151-61.
7. Jerkic M, Vojvodic S, Lopez-Novoa JM. The mecha-
nism of increased renal susceptibility to toxic sub-
stances in the elderly. Part I. The role of increased
vasoconstriction. Int Urol Nephrol. 2001;32:539-47.
8. Evenepoel P. Acute toxic renal failure. Best Pract Res
Clin Anaesth. 2004;18:37-52.
9. Singh NP, Ganguli A, Prakash A. Drug-induced kidney
diseases. J Assoc Physicians India. 2003;51:970-9.
10. Guo X, Nzerue C. How to prevent, recognize, and
treat drug-induced nephropathy. Cleve Clin J Med.
11. Kaler B, Karram T, Morgan WA, Bach PH, Yousef IM,
Bomzon A. Are bile acids involved in the renal dysfunc-
tion of obstructive jaundice? An experimental study in
bile duct ligated rats. Ren Fail. 2004;26:507-16.
12. Perazella MA. Renal vulnerability to drug toxicity.
Clin J Am Soc Nephrol. 2009;4:1275-83.
13. Harty L, Johnson K, Power A. Race and ethnicity in
the era of emerging pharmacogenomics. J Clin Phar-
macol. 2006;46:405-7.
14. Ciarimboli G, Koepsell H, Iordanova M, Gorboulev V,
Durner B, Lang D, et al. Individual PKC-phosphoryla-
tion sites in organic cation transporter 1 determine
substrate selectivity and transport regulation. J Am
Soc Nephrol. 2005;16:1562-70.
15. Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflam-
matory drugs for cancer prevention: promise, perils and
pharmacogenetics. Nat Rev. 2006;6:130-40.
16. Cummings BS, Schnellmann RG. Pathophysiology of
nephrotoxic cell injury. In: Schrier RW, editor. Diseases
of the kidney and urogenital tract. Philadelphia: Lippin-
cott Williams & Wilkins; 2001. p. 1071-136.
17. Kaloyanides GJ, Bosmans J-L, DeBroe ME. Antibiotic
and immunosuppression-related renal failure. In:
Schrier RW, editor. Diseases of the kidney and uro-
genital tract. Philadelphia: Lippincott Williams &
Wilkins; 2001. p. 1137-74.
18. Aleksa K, Matsell D, Krausz K, Gelboin H, Ito S, Koren
G. Cytochrome P450 3A and 2B6 in the developing
kidney: implications for ifosfamide nephrotoxicity.
Pediatr Nephrol. 2005;20:872-85.
19. Enomoto A, Endou H. Roles of organic anion trans-
porters (OATS) and urate transporter (URAT1) in the
pathophysiology of human disease. Clin Exp Nephrol.
20. Ciarimboli G, Ludwig T, Lang D, Pavenstadt H, Koepsell
H, Piechota HJ, et al. Cisplatin nephrotoxicity is criti-
cally medicated via the human organic cation trans-
porter 2. Am J Pathol. 2005;167:1477-84.
21. Lang F. Regulating renal drug elimination. J Am Soc
Nephrol. 2005;16:1535-6.
22. Yang JC, Hayworth L, Sherry RM, Hwu P, Schwart-
zentruber DJ, Topalian SL, et al. A randomized trial of
bevacizumab, an anti-vascular endothelial growth fac-
tor antibody, for metastatic renal cancer. N Engl
J Med. 2003;349:427-34.
23. Eremina V, Jefferson JA, Kowalewska J, Hochster H,
Haas M, Weisstuch J, et al. VEGF inhibition and renal
thrombotic microangiopathy. N Engl J Med. 2008;
24. Sugimoto H, Hamano Y, Charytan D, et al. Neutraliza-
tion of circulating vascular endothelial growth factor
(VEGF) by anti-VEGF antibodies and soluble receptor 1
induces proteinuria. J Biol Chem. 2003;278:12605-8.
25. Gurevich F, Perazella MA. Renal effects of anti-angio-
genesis therapy: update for the internist. Am J Med.
26. Tumlin JA, Finkel KW, Murray PT, Samuels JG, Cot-
sonis G, Shaw AD. Small increases in serum creatinine
are associated with prolonged ICU stays and in-
creased hospital mortality. Paper presented at: Renal
Week; 2005 Nov 10-13; Philadelphia, PA.
27. Jones DP, Spunt SL, Green D, Springate JE. Renal late
effects in patients treated for cancer in childhood: a
report from the Children’s Oncology Group. Pediatr
Blood Cancer. 2008;51:724-31.
28. Zamlauski-Tucker MJ, Morris ME, Springate JE. Ifosf-
amide metabolite chloroacetaldehyde causes Fanconi
syndrome in the perfused rat kidney. Toxicol Appl
Pharmacol. 1994;129:170-5.
29. Pabla N, Dong Z. Cisplatin nephrotoxicity: mecha-
nisms and renoprotective strategies. Kidney Int.
30. Meyer KB, Madias NE. Cisplatin nephrotoxicity.
Miner Electrolyte Metab. 1994;20:201-13.
31. Townsend DM, Deng M, Zhang L, Lapus MG, Hanigan
580 M.A. Perazella and G.W. Moeckel
MH. Metabolism of cisplatin to a nephrotoxin in
proximal tubule cells. J Am Soc Nephrol.
32. Kawai Y, Nakao T, Kunimura N, Kohda Y, Gemba M.
Relationship of intracellular calcium and oxygen rad-
icals to cisplatin-related renal cell injury. J Pharmacol
Sci. 2006;100:65-72.
33. Yilmaz HR, Iraz M, Sogut S, Ozyurt H, Yildirim Z,
Akyol O, et al. The effects of erdosteine on the activ-
ities of some metabolic enzymes during cisplatin-
induced nephrotoxicity in rats. Pharmacol Res. 2004;
34. Chirino YI, Herandez-Pando R, Pedraza-Chaverri J.
Peroxynitrite decomposition catalyst ameliorates re-
nal damage and protein nitration in cisplatin-induced
nephrotoxicity in rats. BMC Pharmacol. 2004;4:20.
35. Faubel S, Ljubanovic D, Reznikov L, Somerset H, Din-
arello CA, Edelstein CL. Caspase-1-deficient mice are
protected against cisplatin-induced apoptosis and
acute tubular necrosis. Kidney Int. 2004;66:2202-13.
36. Ramesh G, Reeves WB. TNF-alpha mediates chemo-
kine and cytokine expression and renal injury in cis-
platin nephrotoxicity. J Clin Invest. 2002;110:835-42.
37. Ramesh G, Reeves WB. TNFR2-mediated apoptosis
and necrosis in cisplatin-induced acute renal failure.
Am J Physiol Renal Physiol. 2003;285:F610-8.
38. Perazella MA. Crystal-induced acute renal failure.
Am J Med. 1999;106:459-65.
39. Pinheiro FV, Imental VC, deBona KS, Scola G, Salva-
dor M, Funchal C, et al. Decrease of adenosine deami-
nase activity and increase of the lipid peroxidation
after acute methotrexate treatment in young rats:
protective effects of grape seed extract. Cell Biochem
Funct. 2010;28:89-94.
40. De Miguel D, Garcia-Suarez J, Martin Y, Gil-Fernadez
JJ, Burgaleta C. Severe acute renal failure following
high-dose methotrexate therapy in adults with
haematological malignancies: a significant number re-
sult from unrecognized co-administration of several
drugs. Nephrol Dial Transplant. 2008;23:3762-6.
41. Celtikci B, Leclerc D, Lawrance AK, Deng L, Friedman
HC, Krupenko NI, et al. Altered expression of meth-
ylenetetrahydrofolate reductase modifies response to
methotrexate in mice. Pharmacogenet Genomics.
42. Giroux L, Bettez P, Giroux L. Mitomycin-C nephro-
toxicity: a clinico-pathologic study of 17 cases. Am J
Kidney Dis. 1985;6:28-39.
43. Cordonnier D, Vert-Pre FC, Bayle F, Alix JL, Couderc
P. Nephrotoxicity of mitomycin C (apropos of 25
case reports). Results of a multicenter survey orga-
nized by the Society of Nephrology. Nephrologie.
44. Blanco C, Sainz-Maza ML, Garijo F, Val-Bernal F, Buelta
L, Fernandez F. Kidney cortical necrosis induced by
mitomycin-C: a morphologic experimental study. Re-
nal Fail. 1992;14:31-9.
45. Colovic M, Jurisic V, Jankovic G, Jovanovic D, Nikolic
LJ, Dimitrijevic J. Interferon alpha sensitisation in-
duced fatal renal insufficiency in a patient with
chronic myeloid leukaemia: case report and review of
literature. J Clin Pathol. 2006;59:879-81.
46. Perazella MA, Markowitz GS. Bisphosphonate neph-
rotoxicity. Kidney Int. 2008;74:1385-93.
47. Sauter M, Juelg B, Porubsky S, Cohen C, Fischereder
M, Sitter T, et al. Nephrotic-range proteinuria follow-
ing pamidronate therapy in a patient with metastatic
breast cancer: mitochondrial toxicity as a pathoge-
netic concept? Am J Kidney Dis. 2006;47:1075-80.
48. Markowitz GS, Apel GB, Fine PL, Fenves AZ, Loon NR,
Jagannath S, et al. Collapsing focal segmental glomer-
ulosclerosis following treatment with high-dose pam-
idronate. J Am Soc Nephrol. 2001;12:1164-72.
49. Lockridge L, Papac RJ, Perazella MA. Pamidronate-
associated nephrotoxicity in a patient with Langer-
hans’s histiocytosis. Am J Kidney Dis. 2002;40:E2.
50. Adami S, Zamberlan N. Adverse effects of bisphos-
phonates. A comparative review. Drug Saf. 1996;14:
51. Braun JP, Rico AG, Benard P, Burgat-Sacaze V, Eghbali
B, Godfrain JC. Urinary gamma-glutamyl transferase in
renal toxicology of the rat. Basis of its use and signif-
icance in acute mercurial nephritis. Toxicology.
52. Schacht RG, Feiner HD, Gallo GR, Lieberman A, Bald-
win DS. Nephrotoxicity of nitroureas. Cancer. 1981;
53. Kramer RA, Boyd MR, Dees JH. Comparative nephro-
toxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclo-
hexyl)-1-nitrosourea (MeCCNU) and chlorozotocin:
functional-structural correlations in the Fischer 344
rat. Toxicol Appl Pharmacol. 1986;82:540-50.
54. Patterson DM, Lee SM. Glucarbidase following high-
dose methotrexate: update on development. Expert
Opin Biol Ther. 2009;10:1-7.
Nephrotoxicity from chemotherapeutic agents 581
    • "Methotrexate and its metabolites, including 7-OH- methotrexate and 4-deoxy-4-amino-N-10-methylpteroic acid (DAMPA), are poorly soluble at an acidic pH [1, 50]. An increase in urine pH from 6.0 to 7.0 increases the solubility of methotrexate and its metabolites by five-to eightfold, and alkalinization is imperative to reduce intratubular crystal formation (precipitation) [1, 50].Thus, administration of fluids with 40 mEq/L sodium bicarbonate is recommended during and after HDMTX administration [1, 7]. A urine pH of 7 or greater should be required before administration of methotrexate to reduce crystal formation. "
    [Show abstract] [Hide abstract] ABSTRACT: Implications for practice: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m(2), is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
    Full-text · Article · Aug 2016
    • "Our results are especially relevant given the fact that AAG levels can vary >10-fold in the human population (at least in lymphocytes) [12, 16, 17] and given the recent surge in the use of PARP inhibitors in combination with chemotherapeutic agents. As nephrotoxicity can be the rate-limiting side effect in a subset of chemotherapeutic agents, these findings may have important clinical relevance [30]. In contrast to our finding that MMS induces nephrotoxicity in Parp1 -/-and Parp-inhibited AagTg mice, several other models of kidney damage have demonstrated protection under conditions of genetic or pharmacologic Parp depletion. "
    [Show abstract] [Hide abstract] ABSTRACT: Nephrotoxicity is a common toxic side-effect of chemotherapeutic alkylating agents. Although the base excision repair (BER) pathway is essential in repairing DNA alkylation damage, under certain conditions the initiation of BER produces toxic repair intermediates that damage healthy tissues. We have shown that the alkyladenine DNA glycosylase, Aag (a.k.a. Mpg), an enzyme that initiates BER, mediates alkylation-induced whole-animal lethality and cytotoxicity in the pancreas, spleen, retina, and cerebellum, but not in the kidney. Cytotoxicity in both wild-type and Aag-transgenic mice (AagTg) was abrogated in the absence of Poly(ADP-ribose) polymerase-1 (Parp1). Here we report that Parp1-deficient mice expressing increased Aag (AagTg/Parp1-/-) develop sex-dependent kidney failure upon exposure to the alkylating agent, methyl methanesulfonate (MMS), and suffer increased whole-animal lethality compared to AagTg and wild-type mice. Macroscopic, histological, electron microscopic and immunohistochemical analyses revealed morphological kidney damage including dilated tubules, proteinaceous casts, vacuolation, collapse of the glomerular tuft, and deterioration of podocyte structure. Moreover, mice exhibited clinical signs of kidney disease indicating functional damage, including elevated blood nitrogen urea and creatinine, hypoproteinemia and proteinuria. Pharmacological Parp inhibition in AagTg mice also resulted in sensitivity to MMS-induced nephrotoxicity. These findings provide in vivo evidence that Parp1 modulates Aag-dependent MMS-induced nephrotoxicity in a sex-dependent manner and highlight the critical roles that Aag-initiated BER and Parp1 may play in determining the side-effects of chemotherapeutic alkylating agents.
    Article · Jul 2016
    • "MTX‑induced nephrotoxicity mainly arises by two mechanisms: Crystal nephropathy and direct tubular toxicity. [6,7] Glucarpidase (carboxypeptidase, CPDG2 enzyme) was approved by the United States Food and Drug Administration in the treatment of plasma MTX concentrations (>1 µmol/L) in patients with delayed MTX clearance due to impaired kidney function. [8] Glucarpidase is a recombinant form of the CPDG2 enzyme, produced via modified Escherichia coli. "
    Full-text · Article · Dec 2015 · Oncotarget
Show more

    Recommended publications

    Discover more