Onco-Nephrology: Renal Toxicities of Chemotherapeutic

Agents
Mark A. Perazella

Summary
Despite dramatic improvements in patient survival and drug tolerability, nephrotoxicity remains an important
complication of chemotherapy. Adverse renal effects occur because of innate drug toxicity and a number of
patient- and drug-related factors. To provide cutting edge care for these patients, nephrologists and oncologists Section of
Nephrology,
must be familiar with the nephrotoxicity of these drugs, particularly their associated clinical and laboratory Department of
manifestations. Rapid diagnosis, targeted treatment, and supportive care are critical to improving care for these Medicine, Yale
patients. Unfortunately, some patients who develop nephrotoxicity will be left with long-term complications such University, New
as chronic tubulopathies and CKD. Onco-Nephrology is a new area that is rapidly expanding and requires a Haven, Connecticut
close working relationship between oncologists and nephrologists.
Correspondence: Dr.
Clin J Am Soc Nephrol 7: 1713–1721, 2012. doi: 10.2215/CJN.02780312
Mark A. Perazella,
Section of
Nephrology,
Introduction with exposure to a potential nephrotoxin. In fact, Department of
Treatment of cancer has undergone many significant Medicine, Yale
nearly 60% of patients with cancer have some form
University, 330 Cedar
advances in recent times. As such, the oncology land- of renal disease (1,2). Direct malignant effects include Street, New Haven,
scape has changed and improved dramatically for myeloma-related kidney injury, infiltration of the re- CT 06520-8029.
many patients. Those patients previously considered nal parenchyma as seen with leukemias and lympho- Email: mark.
therapy failures are now deriving significant benefit mas, urinary tract obstruction from various cancers, perazella@yale.edu
with decreased tumor progression and increased sur- and secondary glomerulopathies (2). Indirect effects in-
vival, often with less severe adverse systemic drug clude true or effective volume depletion from nausea/
effects. Despite this positive advancement in chemo- vomiting, diarrhea, overdiuresis, malignant ascites or
therapeutics for various malignancies, drug nephro- pleural effusions, sepsis, and cardiac involvement,
toxicity remains a complication and sometimes limits which sensitizes the kidney to nephrotoxins by
life-saving therapy (1–3). inducing a prerenal state (2). Also, susceptibility to
As a number of effective but potentially nephrotoxic drug toxicity occurs with metabolic disturbances such
chemotherapeutic regimens are released into clinical as hyperuricemia and hypercalcemia.
practice, oncologists and consulting nephrologists Undoubtedly, the toxicity of the chemotherapeutic
should be familiar with their adverse renal effects. These agent used importantly determines both the develop-
effects include the clinical and histopathologic manifes- ment and type of kidney injury sustained. High doses
tations of renal toxicity (1–6). Clinicians should also be and prolonged therapy increase the chance of renal
well versed in preventive measures available for the injury developing, regardless of the absence of other
various chemotherapy regimens, as well as effective risk factors (2–6). Furthermore, combined exposure of
treatment options for nephrotoxic consequences (1–6). chemotherapeutic agents with other nephrotoxins
The relationship of nephrologists and oncologists in the will raise the risk for kidney injury (7–9).
care of these patients has given rise to the nascent but There are a number of patient-specific risk factors
growing area of Onco-Nephrology. that must be considered with chemotherapy-associated
nephrotoxicity. Many patients are elderly—possessing
reduced total body water and an unrecognized de-
Renal Susceptibility to Chemotherapeutic pressed GFR, higher rates of renal oxidative stress,
Agents and excessive levels of angiotensin-II/endothelin, all
Not all patients exposed to nephrotoxic chemother- of which increase drug nephrotoxicity (10,11). Another
apeutic agents develop kidney injury, suggesting the nonmodifiable risk factor is the host’s underlying ge-
presence of several factors that enhance patient risk for netic makeup, which is likely a powerful explanation
nephrotoxicity. In addition to innate drug toxicity, certain for the heterogeneous response to chemotherapeutic
host characteristics and renal handling of the drug in- agents (12–14). Gene polymorphisms in the renal cy-
crease renal injury. In general, one or more of these factors tochrome P450 enzyme system, which favor reduced
combine to increase risk for kidney injury (Table 1). metabolism and renal excretion, enhance nephrotoxic
Many cancers involve the kidneys either directly or risk. Other examples are loss of function mutations in
indirectly—heightening the risk for kidney injury apical secretory transporters and mutations in kinases

www.cjasn.org Vol 7 October, 2012 Copyright © 2012 by the American Society of Nephrology 1713
1714 Clinical Journal of the American Society of Nephrology
Table 1. Risk factors for chemotherapy-induced
nephrotoxicity
Tumor-related kidney effects
direct renal involvement
myeloma-related kidney injury
renal infiltration (lymphoma and leukemia)
urinary obstruction
neoplasia-associated glomerulopathies
indirect renal involvement
true volume depletion (N/V, diarrhea, and
overdiuresis)
effective volume depletion (cardiomyopathy,
malignant ascites, and pleural effusions)
metabolic effects (hyperuricemia and hypercalcemia)
Innate drug toxicity
high-dose drug exposure and prolonged course of
therapy
insoluble drug or metabolite form crystals within
intratubular lumens
potent direct nephrotoxic effects of the drug or toxin
drug combinations enhance nephrotoxicity
NSAIDs, aminoglycosides, and radiocontrast
Patient factors
older age
underlying AKI or CKD
immune response genes
increased allergic reactions to drugs
pharmacogenetics favoring drug/toxin toxicity
gene mutations in hepatic and renal CYP450
enzyme systems
gene mutations in transport proteins and renal
transporters
Renal drug handling
high blood (and drug) delivery rate to the kidneys
proximal tubular uptake of toxins
apical tubular uptake by endocytosis
or another pathway
basolateral tubular transport through OAT
and OCT pathways
relatively hypoxic renal environment
high metabolic rate of tubular cells in the loop of Henle
increased drug/toxin concentration in renal medulla
and interstitium
biotransformation of substances to ROS causing
oxidative stress
N/V, nausea/vomiting; NSAIDs, nonsteroidal anti-
inflammatory drugs; OAT, organic anion transporter; OCT,
organic cation transporters; ROS, reactive oxygen species.
that regulate drug carrier proteins, which can impair drug
excretion and induce nephrotoxicity by increasing intracel-
lular drug concentrations (13,15).
Last, the renal handling of drugs is another risk factor for
the development of nephrotoxicity. The kidney is exposed
to considerable drug concentrations based on the high renal
blood flow rate—approximately 25% of cardiac output. Sig-
nificant drug uptake occurs in the proximal tubular cells
through both apical uptake and basolateral transport (16,17).
Trafficking of these agents through tubular cells explains, in
part, their nephrotoxicity. The high metabolic rate and hyp-
oxic environment of loop of Henle and medullary collecting
duct cells impart nephrotoxic drug risk (18,19). Metabolism
of drugs by several enzyme systems present in the kidney
favors toxic metabolite and reactive oxygen species formation.
Renal injury may occur, because drug byproducts cause harm
through lipid peroxidation, protein damage, nucleic acid
alkylation or oxidation, and DNA strand breaks (18–20).
Classification of Chemotherapy-Associated Renal
Lesions
There are a number of ways that one can approach
classifying the kidney lesions caused by the various chemo-
therapeutic agents. For example, one could categorize the
chemotherapy-related kidney lesions based on the nephron
sites primarily affected by the drug. Agents that injure the
renal vasculature, glomerulus, proximal and distal tubular
segments, and collecting ducts are described (Table 2), recog-
nizing that all nephrotoxic drugs cannot possibly be covered.
Renal Vasculature: Thrombotic Microangiopathy
Chemotherapeutic agents, such as bevacizumab and
gemcitabine, can injure the renal vasculature and cause
thrombotic microangiopathy (TMA). TMA presents clinically
as microangiopathic hemolytic anemia, thrombocytopenia,
hypertension, and AKI with hematuria and proteinuria,
although renal-limited TMA does occur.
Bevacizumab
Recognition that tumor growth was highly dependent on
pathologic angiogenesis induced by local production of
vascular endothelial growth factor (VEGF) paved the way
for the development of drugs targeting this pathway (21).
This pathway was a logical point of attack to supplement
other tumor-directed therapies—and turned out to be a ben-
eficial addition to the therapeutic armamentarium. Although
there are numerous drugs that target VEGF effects, the anti-
VEGF antibody bevacizumab will be the focus of discussion,
recognizing that there are differences among the agents.
VEGF importantly regulates vasculogenesis and angio-
genesis during development and in disease through reg-
ulation of vascular permeability, endothelial cell migration,
proliferation, and survival (21). This regulation raises the
possibility that these drugs may be associated with ad-
verse effects. In fact, this finding is the case, because a
number of adverse systemic end-organ effects have been
described, including kidney injury. This finding is not sur-
prising, because VEGF is produced by renal visceral epi-
thelial cells and binds to VEGF receptors located on
glomerular endothelium and mesangium, as well as peri-
tubular capillaries (21). Local VEGF production maintains
normal functioning of all of these cells, including injury
repair and cell turnover. Importantly, there is crosstalk
between the glomerular endothelium and epithelium,
maintaining the integrity of the filtration barrier.
The most important renal effects described with anti-
angiogenesis therapy are new or worsened hypertension
and kidney-specific injury, including proteinuria and AKI.
Importantly, the development of hypertension in patients
predicts a better tumor response to therapy (22), and it
should prompt clinicians to continue therapy and control
BP with antihypertensive agents rather than discontinuing
antiangiogenic therapy. Animal experiments documented a
Clin J Am Soc Nephrol 7: 1713–1721, October, 2012
Table 2. Kidney injury associated with chemotherapeutic
agents
Renal vasculature
hemodynamic AKI (capillary leak syndrome)
IL-2, denileukin diftitox
thrombotic microangiopathy
antiangiogenesis drugs (bevacizumab and tyrosine
kinase inhibitors)
gemcitabine and cisplatin
mitomycin C and IFN
Glomeruli
minimal change disease
IFN
pamidronate
focal segmental glomerulosclerosis
IFN
pamidronate
zoledronate (rare)
Tubulointerstitium
acute tubular necrosis
platinums, zoledronate, ifosfamide, and mithramycin
pentostatin, imatinib, diaziquone, and pemetrexed
tubulopathies
Fanconi syndrome
cisplatin, ifosfamide, and azacitadine,
diaziquone, imatinib, and pemetrexed
salt wasting
cisplatin and azacitadine
magnesium wasting
cisplatin, cetuximab, and panitumumab
nephrogenic diabetes insipidus
cisplatin, ifosfamide, and pemetrexed
syndrome of inappropriate antidiuresis
cyclophosphamide and vincristine
acute interstitial nephritis
sorafenib and sunitinib
crystal nephropathy
methotrexate
two- to threefold increase in proteinuria in mice injected
with a single dose of anti-VEGF antibody (23). Renal his-
topathology revealed glomerular endothelial cell swelling,
vacuolization, and detachment, as well as disruption of ep-
ithelial cell slit diaphragms. Immunohistochemistry also
showed downregulation of nephrin, which was partially
restored with administration of recombinant VEGF. The
renal effects of bevacizumab therapy in six patients with
various malignancies were described in detail (24). Renal
findings developed within 3–17 months of drug exposure:
proteinuria occurred in all patients, with five patients hav-
ing at least 1 g/d and two patients having nephrotic-level
proteinuria. Hypertension and AKI developed in 50% of
patients, and all had TMA on kidney histology (Figure 1).
Importantly, proteinuria, hypertension, and AKI generally
improved on withdrawal of bevacizumab.
Although a number of renal lesions have been described
with the antiangiogenesis drugs, the predominant histo-
pathology is TMA. Other lesions described on kidney
biopsy include focal segmental glomerulosclerosis (FSGS),
mebranoproliferative GN, glomerular endotheliosis,
cryoglobulinemic GN, nonspecific immune complex GN,
and acute interstitial nephritis (21,24,25).
Nephrotoxicity of Chemotherapy, Perazella 1715
Figure 1. | A glomerulus exhibits mesangiolysis, endothelial de-
nudation, red blood cell congestion, and glomerular basement mem-
brane duplication in this example of thrombotic microangiopathy.
(Jones methenamine silver stain; original magnification, 3600.) Cour-
tesy of Glen S. Markowitz.
Gemcitabine
Gemcitabine is a cell cycle–specific pyrimidine antago-
nist that is an effective therapy for certain malignancies,
primarily carcinomas of the lung, pancreas, bladder, and
breast. Unfortunately, as with other chemotherapeutic
agents, it is complicated by kidney injury. Numerous
case reports and case series have documented AKI from
gemcitabine, primarily from TMA. In addition, hyperten-
sion, microangiopathic hemolytic anemia, and ischemic
skin lesion may be present. A recent case series of 29 pa-
tients treated with gemcitabine described the various clin-
ical renal manifestations (26). All patients developed AKI;
TMA was seen in four patients who underwent kidney
biopsy. New or worsening hypertension occurred in 26
of 29 patients, whereas edema (21/29) and congestive
heart failure (7/29) also complicated gemcitabine therapy.
Classic systemic TMA occurred in all patients and was
manifested by anemia, thrombocytopenia, and increased
lactate dehydrogenase levels. Suppressed haptoglobin lev-
els (23/26) and schistocytes on peripheral smear (21/24)
were also noted. Urinalysis revealed hematuria/proteinuria
(27/29) and red blood cell casts (n58).
Gemcitabine-associated TMA is relatively rare, with the
major risk factors being previous therapy with mitomycin-C
and total drug dose. Often, it is impossible to predict who will
develop this complication, although new or worsened hy-
pertension may precede other clinical manifestations of TMA.
Unfortunately, therapy is generally limited and mainly sup-
portive, consisting of drug discontinuation, antihypertensive
medications, and dialysis when indicated. Plasmapheresis has
been used with minimal or no success. Renal outcomes are
highly variable. In the largest cases series (26), 19 patients had
full or partial renal recovery, whereas 3 patients developed
CKD and 7 patients had dialysis-requiring ESRD.
Glomerulus: Podocytopathy
IFN
IFN is a glycoprotein synthesized and released by
leukocytes, fibroblasts, T cells, and natural killer cells in
1716 Clinical Journal of the American Society of Nephrology
response to pathogens, such as viruses, parasites, and bac-
teria, as well as tumor cells. It is a protective defense that
allows communication between cells to eradicate infection
or malignant cells. In general, IFN-a and -b reduce viral
replication and protein synthesis in neighboring cells,
whereas IFN-g activates macrophage and MHC expression
(27,28). Based on these characteristics, exogenous IFN has a
number of therapeutic uses. The most commonly used
agent is IFN-a, which is used to treat hepatitis C and B
viruses and various malignancies. IFN-b is used to treat
multiple sclerosis, whereas IFN-g was studied as a treatment
for chronic granulomatous disease but has been abandoned.
Chronic IFN therapy is associated with clinical renal disease,
which seems to be associated primarily with podocyte injury
(27,28). Based on published cases, minimal change disease
has been described with both IFN-a (n56) and -b (n52). The
lesion developed anywhere from 5 days to 22 months after
therapy (27). Nephrotic syndrome with urinary protein lev-
els of 2.3–28 g/d occurred in all patients, whereas AKI com-
plicated the course of two patients. In follow-up ranging
from 53 days to 12 months, complete remission was noted
in all patients, with discontinuation of IFN and steroid ther-
apy in three patients (27,28).
FSGS constitutes another form of podocytopathy that can
complicate IFN therapy. The lesion FSGS-not otherwise
specified has been described in 10 patients treated with IFN
therapy (IFN-a in 9 patients and -g in 1 patient) (27,28). In
these cases, IFN therapy ranged from 19 days to 20 months
and was associated with nephrotic syndrome in all 10 patients,
with proteinuria of 6.3–42 g/d and AKI in 8 patients. With
follow-up ranging from 1 to 16 months in 9 of 10 patients,
complete or partial remission was noted in 4 of 9 patients
with discontinuation of IFN. Six patients received steroids,
of which only two patients benefited with remission.
Collapsing FSGS (Figure 2) also complicates IFN ther-
apy. In 14 patients with this lesion, IFN-a was the causa-
tive agent in 9 patients, whereas IFN-b and -g therapy was
used in 3 and 2 patients, respectively (27,28). IFN exposure
ranged from 1 to 48 months; nephrotic syndrome was
Figure 2. | A glomerulus exhibits global wrinkling and retraction of
the glomerular basement membrane and diffuse swelling and hy-
perplasia of overlying visceral epithelial cells in this example of
collapsing focal segmental glomerulosclerosis. (Jones methenamine
silver stain; original magnification, 3600.) Courtesy of Glen S.
Markowitz.
present in 12 of 13 patients, with proteinuria ranging
from 1.9 to 27 g/d. AKI occurred in 11 patients. Urine
sediment was bland in nearly one-half of the patients,
whereas red and white blood cells were seen in five and
one patients, respectively. Remission was inconsistent and
incomplete in most patients after IFN discontinuation.
With follow-up in 10 patients, which ranged from 2 to
54 months, complete remission was noted in 1 patient
and partial remission was noted in 3 patients, whereas
some improvement in proteinuria and kidney function
was described in 5 patients. Of these 10 patients, 8 patients
received steroids, and 1 patient received cyclophospha-
mide. Thus, although IFN discontinuation sometimes
helps, it is not always associated with remission. Steroids
seem unhelpful, especially in FSGS.
The mechanism of podocyte injury with IFN is incom-
pletely understood. A number of putative mechanisms
have been put forward (27). A direct IFN effect on the
podocyte is possible through receptor binding and activa-
tion that promotes two potential injurious effects: (1) al-
tered cellular proliferation and metabolism of the
pododyte and (2) increased podocyte oxidative capacity
and increased MHC class II antigen expression. Indirect
IFN effects on the podocyte may also contribute to the
development of FSGS. IFNs activate adaptive immune
mechanisms that increase macrophage activation—an ex-
ample is hemophagocytic syndrome, which is associated
with collapsing FSGS. Viral diseases such as HIV and par-
vovirus B19, which increase IFN production, are also as-
sociated with collapsing FSGS. Finally, IFN may enhance
synthesis of pathogenic cytokines such as IL-6 and -13,
which are permeability factors in FSGS and minimal
change disease.
Tubules: Acute Tubular Injury
Cisplatin
Cisplatin is a platinum compound that is an effective
therapy for many carcinomas and sarcomas, as well as
lymphomas. Its major adverse effect is nephrotoxicity,
although ototoxicity also occurs. Both are dose-related
toxicities, causing apoptosis and necrosis of cells (29–32).
Cisplatin injures multiple renal compartments, including
blood vessels, glomeruli, and most commonly, the tubules
(29). Nephrotoxicity is generally reversible, but it can be
permanent. Tubular injury as manifested by AKI and tu-
bular dysfunction syndromes will be described.
Cisplatin’s mechanism of nephrotoxicity is related to its
drug characteristics, its renal handling, and the kidney re-
sponse to the cisplatin molecule (29–32). Chloride at the
cis-position of the molecule is one such factor that pro-
motes kidney injury, whereas the pathway of excretion
through the cell (in through organic anion transporter 1
and out through efflux transporters) potentially increases
intracellular concentrations (Figure 3). After it is inside the
tubular cell, a number of intracellular injury pathways oc-
cur. These pathways include caspase activation, cyclin-
dependent kinases, mitogen-activated protein kinase
activation, and p53 signaling. In addition, cellular injury
also develops from inflammation and oxidative stress,
whereas vascular injury and decreased GFR with ischemic
injury also occur (29–32). These pathways of injury result
Clin J Am Soc Nephrol 7: 1713–1721, October, 2012 Nephrotoxicity of Chemotherapy, Perazella 1717

Figure 3. | Cisplatin (Cis) nephrotoxicity is, in part, related to its uptake by proximal tubular cells. Cis enters cells through organic cation
transporters (OCTs), and when it accumulates within cells, it causes cell injury through multiple mechanisms. Apoptosis and necrosis of tubular
cells result and cause clinical AKI and tubulopathy. CDKs, cyclin-dependent kinases; MAPK, mitogen-activated protein kinase; MRP, multidrug-
resistant protein; NaDC, sodium dicarboxylate; OAT, organic anion transporter; P53, protein 53; Pgp, P glycoprotein; ROS, reactive oxygen
species.

in renal tubular cell apoptosis and necrosis—resulting in
clinical AKI and/or a tubulopathy.
Tubular injury without AKI also complicates cisplatin
therapy and manifests as a number of tubulopathies, which
include isolated proximal tubulopathy (proteinuria and
phosphate wasting) or full-blown Fanconi syndrome (2,29).
Sodium wasting is another consequence of cisplatin therapy,
which can be associated with hypovolemia, orthostasis,
and prerenal AKI. In the distal nephron, cisplatin can im-
pair reabsorption of magnesium, causing refractory hypo-
magnesemia. Finally, water absorption in the collecting
duct can be disturbed, resulting in a form of nephrogenic
diabetes insipidus.
AKI is a dose-related complication of cisplatin—it can be a
functional decline in GFR or caused by TMA, but most
commonly, it is a result of acute tubular injury/necrosis.
Although AKI can recover, renal outcomes such as pro-
gressive CKD from chronic tubulointerstitial fibrosis and
irreversible chronic tubulopathies may result (2,29).
A focus of care for patients receiving cisplatin is pre-
vention of kidney injury (2,29). Forced diuresis with intra-
venous normal saline or hypertonic saline is used to
counteract the toxic effect of chloride on the cis-position
of the molecule. The addition of mannitol to induce a
forced diuresis is sometimes used, but evidence of benefit
is lacking; in some cases, this approach may cause wors-
ened kidney function (33). Amifostine is a glutathione an-
alog taken up by normal cells that blunts cisplatin-induced
cellular injury. It is, however, complicated by nausea and
vomiting. A number of other agents have been used to
reduce nephrotoxicity, such as sodium thiosulfate,
nucleophilic sulfur thiols, neurotrophins, phosphonic acid,
melanocortins, and free oxygen radical scavengers, but their
utility is unclear. In high-risk patients, other platinums such
as carboplatin and oxalaplatin are used based on their less
nephrotoxic profile compared with cisplatin. Two potential
explanations for reduced nephrotoxicity exist. Neither of
these molecules is transported by organic cation transporter
2 (OCT-2), thereby reducing proximal tubular intracellular
concentrations (29–32). In addition, the chloride at cis-position
in cisplatin is replaced by carboxylate and cyclobutane in car-
boplatin and oxalaplatin, respectively, which may further re-
duce toxicity (29–32).
Treatment of toxic renal manifestations is primarily
supportive (2,28). There are no effective therapies to reverse
AKI or tubular dysfunction. Dialysis is reserved for ad-
vanced AKI as manifested by uremia, metabolic disturban-
ces, and hypervolemia. There is no role for dialytic removal
of cisplatin. Maneuvers to correct hypovolemia from salt
wasting (intravenous normal saline or oral sodium chloride)
and address symptomatic hypomagnesemia with intrave-
nous and/or oral magnesium are required. Fanconi syn-
drome is notoriously difficult to treat.
Ifosfamide
Ifosfamide is an alkylating agent used for certain cancers,
including sarcomas, testicular cancer, and some forms of
lymphoma. Ifosfamide’s major adverse effect is kidney in-
jury. Nephrotoxic manifestations include tubulopathies
such as proximal tubular injury or Fanconi syndrome
and nephrogenic diabetes insipidus; additionally, AKI is often
reversible but can be permanent (2,34,35). Histopathology
1718 Clinical Journal of the American Society of Nephrology
reveals features of tubular cell injury/necrosis with swollen,
dysmorphic mitochondria.
The difference in adverse effects for ifosfamide (neph-
rotoxicity) and cyclophosphamide (hemorrhagic cystitis),
which are related compounds, is caused by the major toxic
metabolite that they produce. Acrolein produced by cyclo-
phosphamide is non-nephrotoxic, whereas chloracetaldehyde
produced by ifosfamide injures kidney tissue. At equivalent
doses, ifosfamide produces 40 times more chloroacetaldehyde
than cyclophosphamide (2,34,35). Furthermore, ifosfamide
enters proximal tubular cells through OCT2, whereas cy-
clophosphamide does not (2,35). Risk factors for adverse
renal effects include previous cisplatin exposure, cumulative
dose .90 g/m2, and underlying CKD.
Preventive measures are limited for ifosfamide. Mesna,
which is effective for hemorrhagic cystitis, is of limited
value for ifosfamide-induced kidney injury. Dose reduction
helps but also limits the efficacy of tumor killing. Because
this agent is transported into cells through OCT2, compet-
itive inhibition of this pathway with cimetidine is being
evaluated (35). Treatment, as with many of these agents, is
supportive. Attention to supplementing electrolyte defi-
ciencies, monitoring for progressive CKD, and dialysis as
indicated are important. In addition to CKD and ESRD,
long-term complications include a permanent proximal tu-
bulopathy (1%) and isolated renal phosphaturia in up to
20%. This latter complication may cause osteomalacia or
growth problems in children and exacerbate osteoporosis
in the elderly (2,34,35).
Pemetrexed
Pemetrexed is an antifolate agent that inhibits enzymes
involved in purine/pyrimidine metabolism, thereby im-
pairing RNA/DNA synthesis in tumors such as malignant
Figure 4. | Pemetrexed (Pmx) nephrotoxicity may result from proximal tubular cell uptake of drug through apical (folate receptor-a [FR-a])
and basolateral (reduced folate carrier [RFC]) transporters. After it is inside the cell, Pmx is polyglutamylated, which inhibits drug transport
out of the cell and enhances drug inhibition of folate metabolism. Impaired synthesis of RNA and DNA by cells causes clinical AKI and
tubulopathy. Pmx-glt, polyglutamylated pemetrexed.
mesothelioma and non-small cell lung cancer. This agent is
excreted unchanged by the kidneys (70%–90% in 24 hours),
with a half-life of 3.5 hours (36). Its renal handling may
explain some of the drug’s nephrotoxicity. It is postulated
that pemetrexed enters proximal tubular cells through two
separate pathways. One cell entry site is the basolateral
membrane, where pemetrexed is transported through re-
duced folate carrier, whereas the other is apical drug uptake
through the folate receptor-a transport pathway (Figure 4).
After inside the cell, pemetrexed is polyglutamylated with
two resulting effects. First, with polyglutamylation, the
drug can no longer be transported out of the cell, increasing
intracellular concentrations. Second, the higher drug con-
centrations more fully inhibit folate metabolism enzymes
and impair cellular RNA/DNA synthesis.
Although its major adverse effects are myelosuppression
and neutropenia, reversible AKI has been noted with high-
dose therapy (600 mg/m2). Pemetrexed nephrotoxicity has
been described in several case reports: acute tubular necrosis
(n55), acute interstitial nephritis (n52), nephrogenic diabe-
tes insipidus/renal tubular acidosis (n51), and nephrogenic
diabetes insipidus (n51) (36). A decline in CrCl from 88 to
77 ml/min was reported after four cycles of pemetrexed in a
mesothelioma trial (36). Most patients present with AKI and
minimal proteinuria, which stabilizes with drug discontinu-
ation but can lead to permanent CKD. Renal histology re-
veals primarily chronic tubulointerstitial fibrosis and tubular
atrophy, consistent with a toxic tubular injury (36).
Tubules: Magnesium Wasting
Cetuximab
Cetuximab is a chimeric monoclonal antibody against EGF
receptor (EGFR) used to treat various epithelial malignancies,
Clin J Am Soc Nephrol 7: 1713–1721, October, 2012
including colorectal, head/neck, breast, and lung cancers.
EGF overexpression present in these malignancies reduces
apoptosis and enhances tumor cell growth. Cetuximab has
a 10-fold greater affinity for EGFR than natural ligand, making
it an effective targeted therapy in these cancers. However, one
of the drug’s adverse effects is hypomagnesemia (37–41).
Cetuximab-induced hypomagnesemia results from a renal
leak of magnesium. Magnesium reabsorption in the distal
convoluted tubule is, in part, dependent on EGF binding its
receptor on the basolateral membrane (37,38,41). Activation
of the EGFR sets in motion intracellular signals that stimu-
late the movement of the cation channel transient receptor
potential M6 into the apical membrane, which facilitates the
reabsorption of magnesium from the urinary space into the
cell (37,38,41). Cetuximab competitively inhibits EGF bind-
ing to its receptor (Figure 5), thereby blunting the placement
of transient receptor potential M6 into the apical membrane
and causing renal magnesium wasting (37,38,41).
The incidence of hypomagnesemia with cetuximab in
initial colorectal cancer trials was only 1.8%–5.8% (37,38).
However, a higher incidence was noted when magnesium
levels were measured more rigorously. More than one-half
of patients develop hypomagnesemia with cetuximab, and
nearly 100% of patients have some decline in serum mag-
nesium concentrations (37,38,41). In fact, a meta-analysis
of randomized controlled trials of cetuximab versus other
therapies showed an odds ratio of 4.7 for all-grade hypo-
magnesemia and 5.3 for grade 3/4 hypomagnesemia (42).
In addition, hypokalemia and hypocalcemia occur with
severe hypomagnesemia. Risk factors for hypomagnesemia
include duration of cetuximab therapy, older age, and base-
line magnesium concentration. Panitumumab is also com-
plicated by hypomagnesemia (36%) but of less severe
grade, because only 3% developed grade 3/4 hypomag-
nesemia (1,2).
Figure 5. | Cetuximab (C) is an EGF receptor (EGFR) antibody that causes renal magnesium wasting by competing with EGF for its receptor.
Normally, EGF binds its receptor (EGFR) and stimulates magnesium reabsorption in the distal convoluted cell. EGFR activation is associated
with magnesium absorption through transient receptor potential M6 (TRPM6) in the apical membrane. NCC, sodium chloride cotransporter.
Nephrotoxicity of Chemotherapy, Perazella 1719
Treatment of hypomagnesemia requires intravenous
repletion, because oral magnesium is ineffective and often
complicated by diarrhea. Along with magnesium sup-
plementation, calcium and potassium repletion are also
commonly required. In general, renal magnesium wasting
improves and eventually resolves approximately 4–6 weeks
after discontinuation of cetuximab.
Tubules: Crystal Nephropathy
Methotrexate
The dihydrofolate reductase inhibitor methotrexate is
widely used, especially in high dose, to treat malignancies
such as high-grade lymphomas. Nephrotoxicity is a known
complication of high-dose therapy (1–12 g/m2) but rarely
occurs with long-term conventional dosing (1,2). The in-
cidence is highly variable depending on the patient’s risk
factors and the appropriate employment of preventive
measures, such as intravenous fluids (1,2,43).
Methotrexate and its major metabolite, 7-OH metho-
trexate, are filtered by the glomerulus and secreted into
the urinary space by proximal tubules. AKI is primarily
the result of acute tubular injury from precipitation of
methotrexate/7-OH methotrexate in distal tubular lumens
(2,43). However, tubular apoptosis/necrosis may also de-
velop from oxygen radicals associated with decreased
adenosine deaminase activity (44). AKI incidence, when
defined as grade .2 nephrotoxicity, ranges from 1.8% to
12% (2,43).
Risk factors for nephrotoxicity include intravascular
volume depletion with sluggish urinary flow, acid urine
pH, and underlying kidney disease (GFR,60 ml/min)
(2,42). Based on these factors, prevention is focused on
volume repletion before/during drug infusion, appropri-
ate drug dosing, and alkalinization of the urine (pH.7.1).
1720 Clinical Journal of the American Society of Nephrology
Treatment is comprised of leucovorin rescue at 24–36
hours of methotrexate therapy to reduce nonmalignant
cell injury (2,43,45). Glucarbidase cleaves methotrexate to
noncytotoxic metabolites. It is reserved for use when meth-
otrexate levels are toxic, and there is significant risk for
systemic toxicity (45). High-flux hemodialysis clears the
plasma of methotrexate fairly well (76%) but is associated
with immediate postdialysis plasma rebound (1,2). It may
have a role when severe AKI is present, but it may become
unnecessary with the availability of glucarbidase.
Conclusion
Chemotherapeutic agents have improved cancer patient
survival; however, nephrotoxicity remains an important
complication. A number of patient- and drug-related fac-
tors increase risk for adverse renal events; some events are
modifiable, and others are not. Clinicians must be familiar
with the nephrotoxicity of these drugs, particularly the as-
sociated clinical and laboratory manifestations. Preventive
measures should be used when possible, as well as support-
ive care and available therapies. Some patients will be left
with long-term complications such as chronic tubulopathies
and CKD. Onco-Nephrology is a rapidly expanding area that
requires a close working relationship between oncologists
and nephrologists.
Disclosures
None.
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