Targ Oncol (2009) 4:121–133
DOI 10.1007/s11523-009-0109-x
REVIEW
Renal toxicity of targeted therapies
Ronan J. Kelly & Bertrand Billemont & Olivier Rixe
Received: 10 February 2009 / Accepted: 31 March 2009 / Published online: 6 May 2009
# US Government 2009
Abstract The use of molecular targeted therapies for the
treatment of cancer has increased over the last decade. The
benefits of these compounds in terms of efficacy are often
relatively modest and counter balanced by the occurrence
of significant toxicities. Many of these newer agents used in
clinical practice lack specificity and selectivity and have a
propensity to inhibit multiple targets. The biological
consequences of multi-kinase activity are poorly defined
and numerous class-specific toxicities have been described.
The kidney is an organ where most of these targeted
pathways are expressed. Preclinical data and human renal
biopsies have generated an understanding of the mecha-
nisms involved in how targeted agents can cause renal
toxicity. This review article discusses the observed nephro-
toxicity with this burgeoning class of therapeutics and
reviews both the biological reasons for its occurrence and
possible ways to prevent significant renal damage.
Keywords Targeted therapies . Renal toxicity . Sunitinib .
Bevacizumab . Sorafenib
Introduction
Over the last 10 years, new treatment paradigms incorpo-
rating the use of targeted therapy in the treatment of many
R. J. Kelly : O. Rixe (*)
National Cancer Institute, Medical Oncology Branch,
Center for Cancer Research,
Bethesda, MD 20892, USA
e-mail: rixeo@mail.nih.gov
B. Billemont
CERIA (Centre d’Etudes et de Recours sur les Inhibiteurs de
l’Angiogenese), Cochin Hospital,
Paris, France
types of solid tumors have emerged. An improved
understanding of the molecular biology involved in the
development of cancer has stimulated a dramatic increase in
both research and development for novel antitumor thera-
pies. Several molecular targeted compounds have now been
approved by the US Food and Drug Administration and the
European Medicines Agency for use as single modality or
in combination with conventional cytotoxic chemothera-
pies. Inhibition of the vascular endothelial growth factor
(VEGF) and epidermal growth factor receptor (EGFR)
pathways have been the most successful directions to date
in translating scientific knowledge to clinical benefit for the
treatment of solid tumors [1].
Analysis of large phase II and III clinical trial data has
exposed several limitations for the use of targeted agents.
The demonstration of intrinsic and acquired resistance as
well as the demonstration of specific toxicities involving
the skin, the cardiovascular system and the kidney have
been reported [2]. These observations, in conjunction with
preclinical data, reveal the absence of specificity of these
newer agents. It has been suggested that co-expression of
membrane targets or shared intracellular pathways between
normal tissue and cancer cells may explain the occurrence
of the described adverse events (Fig. 1). Additional
mechanisms of toxicities are also suspected. Monoclonal
antibodies against VEGF or small molecule VEGF-
receptor (VEGFR) tyrosine kinase inhibitors can lead to
significant renal toxicities, including hypertension and
proteinuria. This class-effect will be extensively reviewed
in this article in terms of mechanism, frequency and
clinical implication for the future use of these com-
pounds. In parallel, we will discuss the renal adverse
events observed with preliminary data obtained with
other antiangiogenics blocking a VEGF-independent
pathway.
122 Targ Oncol (2009) 4:121–133

Fig. 1 Schematic representation podocyte

of the nephron and the expres- mesangial cell
sion of the targets VGEF

VEGF-R
FGF-R
HIF2 α
PDGF-R β
Dii4

basement membrane HIF1 α

epithelial cell

VGEF

VEGF-R
NOTCH

MET
PDGF-R β

glomerulus
EGF-R
mesangial cell

VEGF-R

EGF-R
MET

capillaries

VEGF-R

Antiangiogenic compounds and renal toxicity VEGF expression in the adult

In the VEGF era, many selective drugs have been brought
into the clinic. Different strategies have been developed in
two opposite directions: the use of “dirty” drugs with a
large spectrum of activity contrasting with the develop-
ment of very specific compounds, targeting one key
protein involved in the angiogenic process [3]. This
duality is not restricted to VEGF-VEGFR inhibition, but
can be applied to other targeted agents including anti-EGFR
molecules [4]. In clinical trials, highly specific or selective
inhibition of only one of the kinases involved in the
signaling pathways has been associated with sporadic or
limited responses. The selective versus multiple inhibitions
have significant potential implications in terms of activity
and toxicity.
VEGF is strongly expressed embryologically, playing a
critical role in new blood vessel formation. In adults, VEGF
is a key regulator of many physiologic processes such as
wound healing, bone repair and the response of skeletal
muscle to exercise [5]. It also plays a central role in
maintaining a normal menstrual and reproductive cycle
with monthly changes occurring in the uterus, ovary and
breast [6]. VEGF is upregulated in several patho-
physiologic processes (see Table 1). Maharaj et al. have
proposed a classification involving three levels of expres-
sion of VEGF in normal tissues. In the “sparse cellular”
expression group, including brain, retina and testes, VEGF
is expressed primarily by pericytes and vascular stromal
cells [7]. The “intermediate group” of VEGF expression
Targ Oncol (2009) 4:121–133 123

Table 1 Occurrence of proteinuria in clinical trials with bevacizumab

Treatment Cancer No of patients Proteinuria No. of patients (%) Reference

All grades Grade 3–4

B+C BC 229 51 (22.3%) 1 (0.4%) Miller et al. 2005 [85]
B+P BC 365 - 13 (3.5 %) Miller et al. 2007 [86]
B+E BC 38 8 (21%) 0 Dickler et al. 2008 [87]
B + Cy + C BC 46 15 (32%) 1 (0.2%) Dellapasqua et al. 2008 [88]
B all level RCC 76 40 (52.3%) 5 (6.5%) Yang et al. 2003 [89]
3 mg/kg 39 25 (32.5%) 3 (3.9%)
10 mg/kg 37 15 (19.7%) 2 (2.6%)
B + INF RCC 327 59 (18%) 22 (7%) Escudier et al. 2007 [90]
B + INF RCC 366 - 56 (15%) Rini et al. 2008 [91]
B+E RCC 51 (B) - 3 (5.7%) Bukowski et al. 2007 [92]
51 (B + E) - 16 (31%)
B+P+C NSCLC 66 21 (32%) 1 (1.5%) Johnson et al. 2004 [93]
B+P+C NSCLC 434 NA 13 (3.1%) Sandler et al. 2006 [94]
B+E NSCLC 32 9% 0 Herbst et al. 2005 [95]
B + E vs B NSCLC 78 0 0 Herbst et al. 2007 [96]
B + XELOX Vs B + FOLFOX CCR 141 vs 72 - 20 vs 15 Hochster et al. 2008 [97]
B + XELOX vs B + FOLFOX CCR 350 vs 349 4 (<1%) 0 Saltz et al. 2008 [98]
B + XELOX +/- Cetux CCR 192 vs 197 82 (21%) 21 (5%) Tol et al. 2008 [99]
IFL +/- B CCR 393 26.5 % 0.8 % Hurwitz et al. 2004 [100]

B (bevacizumab), C (Capecitabine), P (Carboplatin), E (Erlotinib), Cy (cyclophosphamide), INF (Interferon), Xelox (Capecitabine + oxaliplatin),
FOLFOX (Oxaliplatin + 5FU), Cetux (Cetuximab)

involves cardiac and skeletal muscles. In the “highest
density” group, VEGF is expressed on the epithelia in
contact with the fenestrated vasculature of tissues such as
the glomerulus, choroid plexus, liver and pancreas. Inter-
estingly, endothelial cells do not generally express
VEGF [8]. As an exception, aortic endothelial cells
express VEGF, but not the vena cava [9]. The role of
expression of VEGF in this large blood vessel is unknown.
VEGF is potentially expressed in every tissue in the adult,
and its receptor (VEGFR2) is also expressed in close
proximity to the VEGF source [10].
Function of VEGF in the adult
VEGFR1 and VEGFR2, and is essential in many physio-
logic processes. VEGF induces and maintains fenestration.
Fenestrae on endothelial cells are discontinuities that
facilitate movement of particules in and out the circulation
[12].
Anti-VEGF agents and their associated renal toxicity
Despite its central role in many normal physiologic
functions VEGF is also a key regulator of tumor angiogen-
esis. This finding has led to the development of several
VEGF-targeted agents that include neutralizing monoclonal
antibodies [13] (Fig. 2).

The function of VEGF appears to be pleiotropic. (1) The Bevacizumab

low expression of VEGF seen in the vasculature of tissues
having barrier functions (e.g., retina, brain, testes) may
contribute to the impermeability of these vessels [11]. (2)
Inhibition of VEGF leads to an alteration of the microvas-
culature and in blood vessel regression in a number of
normal tissues. (3) VEGF plays an integral role in the
normal functioning of fenestrated endothelial cells. These
cells are found in many endocrine tissues as well as in the
kidney, the choroid plexus and the gastrointestinal tract.
The permeability of endothelial cells is mediated via both
Bevacizumab is an anti-VEGF165 humanized monoclonal
antibody approved by the US Food and Drug Administra-
tion for the treatment of metastatic renal cell carcinoma but
also colon, breast and non-small cell lung carcinoma in
combination with chemotherapy. Bevacizumab is specific
for VEGF (also referred to as VEGF-A) but does not
neutralize other members of the VEGF family (VEGF-B to
E) [14]. Monoclonal antibodies, including bevacizumab,
have emerged as a class of specific and selective anti-cancer
124
Fig. 2 Site of action of VEGF VEGF-R2 VEGF-R3
and VEGFR inhibitors on endo- VEGF-R1
thelial and cancer cells
endothelial cell
tumor
molecules [15]. The mechanism of action of bevacizumab
has been extensively studied [16]. The current view of its
angiogenesis inhibition involves a complex series of events
including the classic sprouting angiogenesis inhibition
(including inhibition of new blood vessel growth and
vascular regression), modification of vessel permeability
and vascular constriction, direct effect on tumor cell
function, offsetting of effects of chemotherapy induction
of VEGF levels, but also bone marrow-derived endothelial
progenitor cells inhibition. Induction of endothelial cell
apoptosis is one the major effect of bevacizumab. VEGF
plays a significant role in numerous pro-survival pathways
in endothelial cell homeostasis [17] including activation of
BCl-2, Akt and survivin.
The safety profile of bevacizumab has been studied in
randomized control clinical trials. Clinically relevant side
effects relating to bevacizumab include hypertension,
proteinuria, arterial thromboembolic events, wound healing
complications and gastro-intestinal perforation [18].
One of the most common is proteinuria, which is
reported in 21% to 64% of patients. Nephrotic-range
proteinuria denotes structural damage to the glomerular
filtration barrier and occurs in 1% to 2% of bevacizumab-
treated patients [19]. Acute renal deficiency or creatinine
elevation was rarely reported [20]. More recently, several
cases of thrombotic micro-angiopathy have been docu-
mented. This condition is associated with arterial hyperten-
sion, acute renal deficiency, proteinuria and hematuria [21].
Targ Oncol (2009) 4:121–133
PDGF-R HIF1
NOTCH
pericyte C-KIT
MET
FR
G
VE
tumor cell
Raf
HIF MEK
Erk
PDGF-R
VEGF-R
The occurrence of renal toxicities demonstrates the
absence of total selectivity for tumor cell targeting and
has been extensively documented by Eremina et al. [22].
Putative causes of nephrotoxicity have been suggested
including an indirect effect of the therapy (called “off-
target” toxicity related to immunologic disorders related to
the monoclonal antibody) or “on-target” effects due to the
co-expression of VEGF on the normal kidney. The role of
other co-morbidities and drug interactions need to be
further identified to determine the individual patient
susceptibility to bevacizumab toxicity.
In a very elegant publication, Eremina et al. [23]
reported six cases of patients with proteinuria associated
with thrombotic microangiopathy (TMA) after bevacizu-
mab administration. From this clinical evidence, the authors
developed an animal model to document the mechanism of
renal toxicity. Using a knock-out mice model, local genetic
ablation of VEGF production in the kidney mimics the
TMA observed in humans. In this study, a lack of VEGF
production by podocytes was obtained and mice developed
proteinuria after a period of 4 weeks followed by the
occurrence of hypertension. The kidneys of all the KO mice
were pale and shrunken, while electron microscopy of the
glomeruli displayed typical features of TMA. When disease
progressed the following alterations were observed: (1)
altered podocytes morphology, (2) swollen endothelial cells
and (3) alteration of fenestrated endothelium. Interestingly,
schistocytes were found in blood smears from more than
Targ Oncol (2009) 4:121–133
50% of the animals. These findings are similar with those
reported in humans. They suggest a critical role for
VEGF within the glomerulus. No involvement of the
peripheral microvasculature was reported and extra-renal
circulating VEGF levels were not affected in this KO
mice model. The authors conclude that renal damage
induced by bevacizumab is a direct reduction of
glomerular VEGF production, or as previously described
an “on-target” effect of the drug. It appears that
Bevacizumab administration is associated with damage
to the glomerular endothelium suggesting that local
VEGF-A production is required for the maintenance of
the integrity of this specialized vascular bed and ulti-
mately there is interference with the critical cross-talk
between podocytes and endothelium in the glomerulus. A
similar observation has been reported with preeclampsia, a
pregnancy-specific disorder that complicates approximate-
ly 5% of all pregnancies, making it perhaps the most
common glomerular disease in the world. It is character-
ized by new-onset hypertension and proteinuria, second-
ary to the previously described bevacizumab induced
alterations that occur in the glomerulus. Recent evidence
suggests that these alterations in the glomerulus are
mediated by an extra-renal overproduction of a soluble
VEGF receptor that denies normal functioning glomerular
endothelial cells of VEGF. This subsequently leads to
cellular injury and disruption of the filtration apparatus
with subsequent proteinuria [24].
Drug induced hypertension is most likely secondary to
the renal toxicity of bevacizumab and it is a clinical
symptom associated with thrombotic micro-angiopathy
[25]. In addition, VEGF starvation reduces endothelial
nitric oxide production, which increases blood pressure by
causing vasoconstriction. Hypertension can also be second-
ary to kidney injury or vascular rarefaction, resulting in an
increase of systemic resistance [26]. These observations
strongly support the absence of absolute tumor selectivity
of anti-VEGF agents, emphasizing the critical role that
VEGF plays in normal tissues homeostasis.
Sunitinib
Sunitinib is an oral multikinase inhibitor which targets
VEGF-R, PDGF-R, and c-kit [27]. In the initial phase I
study, Faivre et al. reported a case of grade 3 hypertension,
associated with a paradoxical 30-fold increase circulating
VEGF level [28]. In a phase II study conducted in renal cell
carcinoma, creatinine elevation was present in 14% of the
63 patients. In addition, grade 2 (2 patients, 3.2%) and
grade 3 (1 patient, 1.6%) hypertension were respectively
reported in this analysis. In the large phase III study (renal
cell carcinoma), elevation of creatinine level was reported
in 66 patients (17.6 %) and grade 3 (0.3%) in one patient
125
[29]. Similarly to bevacizumab, 2 cases of thrombotic
micro-angiopathy were also reported [30].
Sorafenib
Sorafenib is a tyrosine kinase inhibitor of VEGF-R, PDGF-
R, C-kit and BRAF. In a phase II study conducted for the
treatment of hepatocellular carcinoma, proteinuria was
reported in 19 patients (41%) [31]. These results were not
replicated in the phase III study, as hypophosphastemia was
the only renal toxicity reported [32].
Grade 1 creatinine elevation was reported in a phase II
study in prostatic patients treated with sorafenib [33]. In
addition, a similar study performed in 22 androgen-
independent prostate cancer patients revealed 3 cases of
hypocalcemia, 2 cases of hyponatremia and 2 cases of
hypophosphastasemia [34]. No significant renal toxicities
were reported in the large phase III TARGET study
conducted in metastatic renal cell carcinoma [35]. Izzedine
et al. recently reported interstital nephritis associated with
skin toxicity [36]. The combination of sorafenib and
bevacizumab was associated with proteinuria and hyper-
tension and was reported as the dose limiting toxicity in a
recently published phase 1 study [37].
VEGF-independent inhibition
HIF-1alpha inhibition
Hypoxic-inductible factors (HIFs) are heterodimeric basic
helix-loop-helix/PAS proteins that induce the transcription
of a diverse array of genes to affect the hypoxic response.
HIFs are composed of an α subunit (HIF-1α, HIF-2 α and
HIF-3 α) and a β subunit (HIF-1β or ARNT) [38]. There
are multiple splice variants of HIF-1 α and HIF-3 α, with
dominant negative proteins being produced in some tissues.
HIFs are key elements required to mediate cellular
adaptation to low O2 by activating the transcription of
target genes involved in angiogenesis, metabolism, and
extra-cellular matrix remodeling [39]. Overexpression of
HIFs promotes tumorigenesis, but paradoxically, there is
genetic evidence for a tumor suppressor role for HIF-1α.
The critical role of HIFs in the development of renal cell
carcinoma is demonstrated by an increase in HIF-2α
expression via c-Myc activation in sporadic VHL-deficient
clear cell RCC and is the basis for the current development
of anti-HIF-1α targeted therapies in this setting.
In human tissues, HIF-1α messenger RNA expression is
generally ubiquitous with high expression in the kidneys
(predominantly in the cortical and medullary ducts, and
glomerular cells) [40]. The expression of HIF-2α is
detectable in podocytes, as well as in cortical and medullary
endothelial and interstitial cells. HIF-2α may play a role in
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the development of the tubular system, but the real role of
HIFs in nephrogenesis needs to be further delineated.
Chronic hypoxia has been described as the final common
pathway to end-stage renal failure, and HIFs are seen as the
master switch of the hypoxic adaptation response. HIFs
often have contrasting effects on the kidneys, from the
beneficial cytoprotective effect seen in acute ischemia-
reperfusion injury to a detrimental role in inflammation
with a profibrotic effect in chronic renal hypoxia.
Recently, the first in human phase I study with an anti-
HIF1α RNA antagonist has been reported. EZN-2968 is a
third generation oligonucleotide (locked nucleic acid). In
vivo, this compound has a broad distribution into major
organs including the kidneys [41]. No renal toxicities have
been reported in mice. In the phase I study conducted in 18
patients, one patient experienced grade 3 hypertension.
Interestingly, no proteinuria or renal dysfunction has been
reported to this point [42].
Notch inhibition
The notch signaling pathway plays a pivotal role in
angiogenesis but appears to be both independent of and
run parallel to the well described VEGF/VEGFR system
[43]. Notch receptors comprise a family of transmembrane
receptors, their ligands and the subsequent transcription
factors. They are expressed by various cell types and are
involved in cell differentiation, cell fate, and cell prolifer-
ation. The four membrane receptors (notch 1, 2, 3 and 4)
interact with transmembrane ligands (e.g., jagged 1, Dll4).
Dll4 is expressed exclusively by endothelial cells and
represents a major stimulator (via its notch receptor) of
angiogenesis [44]. Knockout of only Dll4 in mice is lethal to
the embryo and is seen as an essential signal for normal
vascular development. The notch-Dll4 complex is upregu-
lated in tumor vasculature and drugs targeting this pathway
are in early phases of preclinical development. Studies
involving neutralizing antibodies against Dll4, and inhibitors
of the notch receptor are ongoing. Preclinical data suggest
that drugs that target the Dll4-ligand can paradoxically lead
to an increase in immature tumor vasculature, however, these
new vessels are unable to support tumor growth [45].
Podocytes are a type of epithelial glomerular cell
involved in the ultrafiltration process that occurs in the
kidney [46]. Alteration of several podocyte proteins has
previously been described in the development of glomer-
ulosclerosis. The notch pathway plays a crucial role in renal
development during embryogenesis [47]. There is however
little active notch1 detected in mature adult kidneys under
normal conditions. Activation of the notch pathway in
mature podocytes has been associated with glomerular
disease, and pharmacological inhibition of notch cleavage
can prevent podocyte apoptosis and albuminuria [48].
Targ Oncol (2009) 4:121–133
Similarly, the notch signaling pathway is overexpressed in
the proximal tubules and is involved during acute injury
such as tubular necrosis. It is clear that stimulation of the
notch pathway in the normal healthy adult kidneys can lead
to complications. Further studies are required to determine
if notch activation is either a response mechanism or a
primary cause of the renal disease.
At present inhibition of the notch pathway for the
treatment of cancer is still conceptual. Further studies are
required to determine the exact role notch plays in terms of
nephroprotection or nephrotoxicity. Future notch receptor
inhibitions will also require a high level of specificity as
different notch receptors are responsible for different
functions with notch2, but not notch1, being required for
fate acquisition in the mammalian nephron [49].
Epidermal growth factor inhibition and renal toxicity
The epidermal growth factor receptor (EGFR) is part of a
family of four tyrosine kinases whose aberrant activity
plays a key role in growth and metastasis of solid tumors:
epidermal growth factor receptor (EGFR; erbB-1), erbB-2
(Her2 or neu), erbB-3, and erbB-4 [50]. There are six direct
binding ligands known for EGFR, including EGF, trans-
forming growth factor, amphiregulin, betacellulin, epiregu-
lin, and heparin-binding EGF. Ligand binding to the
extracellular domain of EGFR leads to receptor dimeriza-
tion, causing the activation of downstream signaling path-
ways by activation of the cytosolic kinase domain of the
receptor tyrosine kinase and cross-autophosphorylation of
the receptors [51].
It has also been shown that erbB-2 is the preferential
heterodimerization partner of EGFR compared with the rest
of the erbB family members [52]. At least three main
pathways of EGFR signaling supporting cancer develop-
ment and progression can be identified. They include (1)
phosphatidylinositol 3-kinase (PI3K) leading to Akt activa-
tion and suppression of apoptosis, (2) Grb2 and Sos leading
to the activation of p21ras driving the cell cycle, and (3)
phospholipase C-γ1 phosphorylation leading to PIP2-
related actin reorganization.
Numerous anti-EGFR agents have been developed and
are used routinely in clinical practice for the treatment of
several solid tumors including colon cancer, lung cancer
and head and neck tumors. Routinely used drugs include
small molecule tyrosine kinase inhibitors (e.g., erlotinib,
gefitinib) or monoclonal antibodies (e.g., cetuximab,
panitinumab). HER2 (erbB-2) overexpression is associated
with an aggressive phenotype in breast cancer. Trastuzumab
and lapatinib have successfully been developed for the
treatment of metastatic and locally advanced breast cancer
overexpressing HER2.
Targ Oncol (2009) 4:121–133
In the kidney, EGFR is expressed mainly in distal,
collecting, and proximal tubules. It has also been detected
in glomerular capillary walls and other vascular compo-
nents (e.g., mesengial and parietal epithelial cells, peritub-
ular capillaries and arterioles). Functionally, EGFR has a
dual role in renal epithelia [53]: (1) reactive species-
dependent activation of EGFR leads to cell death in renal
proximal tubule cells exposed to cisplatin, and (2) func-
tional inactivation of EGFR in renal proximal tubular cells
reduces tubular-interstitial lesions after renal injury [54].
Once activated the EGFR/Ras/MEK/ERK pathway serves a
pro-survival role in renal epithelia under moderate oxida-
tive stress. Severe oxidative stress induced by ischemic
conditions can result in necrotic death via a mechanism that
disconnects EGFR from ERK activation in both renal
proximal and distal cells. These observations explain the
occurrence of renal toxicities after the use of EGFR
modulators in humans. However, EGFR expression level
is lower in normal epithelial tissues in comparison with
cancer cells. HER2 is commonly expressed in fetal
epithelial cells of the human kidney and to a lesser
degree in normal human adult kidneys. HER2 is
implicated in the collecting tubular cyst formation and
enlargement in polycystic kidney disease in concert with
EGFR.
EGFR inhibitors
Erlotinib is a commonly used epidermal growth factor
receptor (HER1/EGFR) tyrosine kinase inhibitor [55]. It
inhibits ATP binding to HER1/EGFR tyrosine kinase in
normal and tumor cells. The tyrosine kinase of HER1/
EGFR is a target for therapeutic intervention in many
malignancies including ovarian, head, neck, lung, breast,
bladder and other squamous cell cancers. The most
common side effects in patients receiving erlotinib are skin
rash, fatigue and diarrhea. Other reported side-effects
included interstitial lung disease. No renal toxicity has
been described with this agent. In the phase I and phase II
studies conducted in combination with bevacizumab,
hypertension, proteinuria and renal dysfunction have been
reported, but do not significantly differ between the
combination arm and bevacizumab arm. Miller et al. [56]
recently reported that patients with renal dysfunction can
tolerate a full dose of erlotinib (150 mg daily) and seem to
have an erlotinib clearance similar to patients without organ
dysfunction.
Gefitinib is similar to erlotinib and is also an orally
active small-molecule tyrosine kinase inhibitor of EGFR.
Preclinical data from the phase I study of gefitinib did not
indicate any clinically significant changes in renal param-
eters. The toxicity profile is similar to erlotinib, including
diarrhea, rash, acne, dry skin, nausea, and vomiting. Two
127
published case reports of gefitinib-induced renal toxicities
have highlighted a incidences of nephrotic syndrome and
tubulointerstitial nephritis after the administration of gefi-
tinib. In the first case, mild infiltration of lymphocytes have
led to sclerotic changes in renal glomeruli and suggest an
immune reaction to gefitinib [57]. In the second case, after
a two-year period of gefitinib administration, immunofluo-
rescence revealed a predominance of mesangial IgA and C3
deposits, suggesting an IgA nephropathy [58]. It has been
suggested that long-term administration of gefitinib could
inhibit the normal turnover of tubular epithelial cells,
leading to interstitial damage [59].
Cetuximab, a monoclonal antibody against the extracel-
lular domain of the EGFR, has been approved for the
treatment of metastatic colon carcinoma in combination
with irinotecan, and more recently for the treatment of
locally advanced head and neck carcinoma in combination
with radiation therapy [60]. No renal toxicity, including
proteinuria, hypertension or renal dysfunction, has been
reported with this agent. In a recent survey conducted by
the EORTC in patients with head and neck carcinoma
treated with cetuximab, the authors do not report renal
dysfunction [61].
HER2 inhibitors
Trastuzumab is a recombinant monoclonal antibody
directed against the extracellular domain of the HER2
protein [62]. Data from phase I to III clinical trials and from
post marketing surveillance has not highlighted significant
renal toxicities [63]. Trastuzumab is however teratogenic
when administered during pregnancy with normal fetal
development of the kidneys being impaired [64].
Lapatinib is a tyrosine kinase inhibitor approved for use
in combination with capecitabine to treat advanced or
metastatic breast cancers overexpressing HER2. Lapatinib
is a dual inhibitor of EGFR and HER2, and no renal
adverse events have been reported in the 44 published
clinical studies [65].
Other HER2 inhibitors (pertuzumab, ertumaxomab and
trastuzumab-MCC-DM1) are in early phases of develop-
ment but no nephrotoxicity has as yet been reported.
Other targeted therapies and renal toxicity
Imatinib is a tyrosine kinase inhibitor that targets the
Abelson (Abl) tyrosine kinase with high selectivity.
Imatinib but also inhibits CD117 (c-Kit) and platelet-
derived growth factor (PDGF)-α and PDGF-β at concen-
trations of approximately 0.5 µmol/l in vitro. PDGF-β and
c-kit are both expressed in the kidney. PDGF-β expression
has been reported in proximal tubes, mesangial and
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interstitial cells [66]. c-Kit is also expressed in both
proximal and distal tubules. In the initial large study
conducted by Druker et al in chronic myeloid leukemia,
renal failure was reported in less than 1% of the patients
[67]. When a higher dose (800 mg daily) was tested in
patients with renal cell carcinoma, the occurrence of grade
II renal toxicity was higher (14%) [68]. In addition, several
cases of acute tubular necrosis were reported and docu-
mented with renal biopsies. Francois recently reported a
case of modest renal impairment associated with a Fanconi
syndrome [69]. Electronic microscopy showed vacuoles in
some tubular cells, suggesting proximal tubular injury.
Imatinib induced tubular necrosis has also been reported by
Foringer and Pou [70], necessitating hemodialysis. In
addition, one case of thrombotic microangiopathy (TMA)
with renal and extra-renal expression has been reported,
requiring definitive hemodyalisis [71]. Patients with preex-
isting renal dysfunction should be monitored closely for the
development of renal failure and tubular toxicity when
taking imatinib.
Nilotinib is a second-generation imatinib analog with a
similar spectrum of activity. It is at an earlier phase of its
development than imatinib but as yet no renal toxicity has
been reported [72].
Dasatinib is the first of the second-line ABL inhibitors
approved by the Food and Drug Administration. This is a
multi-kinase inhibitor that targets SRC (a family of proto-
oncogenic tyrosine kinases) and many other kinases besides
BCR-ABL [73]. No renal toxicity has been currently
published.
MET tyrosine kinase is a cell surface receptor for
hepatocyte growth factor (HGF). HGF conveys a combina-
tion of pro-migratory, mitogenic and anti-apoptotic signals
[74]. MET is a candidate for targeted therapeutic interven-
tion. Several genetic alterations including translocation,
amplification or activating mutations have been reported in
several types of malignancies. Germline MET gene
mutations and somatic MET gene mutations are the key
molecular events described respectively in hereditary
papillary renal cell carcinoma and in its sporadic form.
HGF (and the ensuing activation of MET) plays a critical
role in the control of tissue homeostasis (including the
normal kidney) but also in several degenerative diseases
including progressive nephropathies [75]. Several strategies
have been pursued to inhibit MET. HGF or MET
neutralizing antibodies and small-molecule MET inhibitors
are currently under investigation in phase I and II studies.
XL880 clinical trials began in 2005 and phase II trials are
currently in process. In the papillary RCC phase II study, a
15% (including 8% grade 3) rate of hypertension (mainly
associated with proteinuria) has been reported [76]. This
can be related to the MET inhibition, and also to the
additional tyrosine kinases inhibition including VEGFR2.
Targ Oncol (2009) 4:121–133
Interestingly, no renal toxicities have been reported so far
with the anti-MET antibodies. However, as Met regulates
and mediates maintenance of the normal adult collecting
duct, putative renal toxicities of MET inhibitors are
expected.
Newer agents involving molecular targeted therapies
affecting many key novel pathways—HDAC (histone
deacetlyase inhibitors), HSP90 (heat shock protein 90
inhibitors), PARP (Poly (ADP-ribose) polymerase-enzyme
inhibitors), Hegdehog, IGFR, PI3k, AKT, and Ras inhib-
itors—are currently under pre-clinical or clinical develop-
ment. No specific renal toxicities have been reported as yet
but detailed safety analysis will be required as many of
these cellular pathways represent important signals for renal
cell homeostasis.
Recommendations for the management of renal
toxicities
Renal impairment can be assessed by measuring both
glomerular and tubular functions in the kidney. The
measurement of creatinine clearance reflects the glomerular
filtration rate. In daily clinical practice, renal function is
estimated by the Cockroft formula (Cockcroft, Gault 1976)
and more accurately by the MDRD (Modification of Diet in
Renal Disease) formula [77]. Urinary albumin excretion
(determined by urine dipstick testing, spot urine sampling,
urinary protein/creatinine ratio (UPC) or 24-hour protein
determination) explores the integrity of the glomeruli.
Tubular function is assessed by the excretion of glucose,
pH, osmolarity, urinary uric acid, calcium, phosphorus and
magnesium. Based on these parameters, a grading system
of renal toxicities has been established and is available in
the National Cancer Institute Common Terminology Crite-
ria document. This classification focuses on an alteration of
the glomerular filtration rate and metabolic disorders (Table 2).
Patients with cancer have an increased risk of developing
renal failure [78]. A detailed history evaluating specific co-
morbidities (e.g., diabetes, hypertension, nephrectomy)
needs to be performed at baseline. In some cases, cancer
may cause obstruction in the urinary tract or lead to a direct
infringement of the renal parenchyma. Tumors may also be
associated with metabolic abnormalities (e.g., hypercalce-
mia, hepato-renal syndrome) [79]. Finally, the prior use of a
conventional first line anti-cancer agent (e,g,, platinum
salts) can lead to nephrotoxicity and impaired kidney
function even before initiating a second or third line
targeted therapy.
Nephrotoxic risk must be evaluated before starting any
anti-angiogenic treatment. This includes a thorough history,
clinical examination and laboratory investigations evaluat-
ing for renal dysfunction. Following the initiation of
Targ Oncol (2009) 4:121–133 129

Table 2 Grading for renal toxicities

Grade Creatinine Proteinuria Glomerular filtration rate

1 Normal −1.5×ULN 1+or 0.15–1.0 g / 24 h <75–50% LLN

2 1.5–3.0×ULN 2+to 3+or >1.0–3.5 g/24 h <50–25% LLN
3 3.0–6.0×ULN 4+or >3.5 g/24 h <25% LLN, chronic dialysis non indicated.
4 6.0×ULN Nephrotic syndrome Chronic dialysis (or renal transplant) indicated.

ULN: Upper Limit Normal LLN: Lower Inferior Normal

treatment patients should be monitored every two weeks
both clinically and with bioassays and urine testing. In the
presence of abnormal blood and urine values or signs
suggestive of thrombotic micro-angiopathy, an expert
nephrological opinion should be sought (Table 3).
Blood pressure and proteinuria must be monitored
before, during and after this medical treatment, even in a
palliative setting. Intervention must be both timely and
aggressive to avoid consequences of acute hypertension.
No clear consensus for the choice of anti-hypertensive
agents has been established. In the presence of hyperten-
sion, careful monitoring of blood pressure is recommended.
Patients during therapy should be advised to purchase a
home blood pressure monitoring system. Blood pressure
should be checked at home at least once daily (in the
morning), and patients should be advised to contact the
clinic if they note elevated blood pressure levels.
Antiangiogenic-related hypertension should be treated with
oral antihypertensive therapy. After a titration for effect, if
blood pressure control is less than optimal, the patient
should be referred to a nephrologist. Standard oral
antihypertensive agents used to manage antiangiogenic-
related hypertension include angiotensin-converting en-
zyme (ACE) inhibitors, beta blockers, calcium channel
blockers, and diuretics. The presence of hypertension and
proteinuria would favor the use of ACE inhibitors or
angiotensin receptor blockers, due to their renal protective
effect with the restoration of nephrin expression. Calcium
channel blockers may interact with small molecules through
cytochrome CYP3A4 and could expose patients to a risk of
underdosage or overdosage of the antiangiogenic molecules.
Conclusion
Analysis of the literature reveals that significant renal
toxicities secondary to targeted molecular therapies exist.
This phenomenon underlines the absence of selectivity of

Table 3 Summary of renal tox-

icities associated with molecular Class Symptoms Nephron damage (biopsy proven)
targeted therapies
ANTIANGIOGENICS
VEGF inhibitors Hypertension/Proteinuria Glomerulonephritis
TMA
VEGFR inhibitors Hypertension/Proteinuria Glomerulonephritis
Interstitial Nephritis
HIF inhibitors NR
Notch inhibitors ND
OTHERS
HER inhibitors
EGFR inhibitors Proteinuria Acute Tubular Necrosis
IgA nephropathy
HER2 inhibitors NR NR
C-KIT inhibitors Hypertension/Proteinuria TMA
Acute Tubular Necrosis
MET inhibitors Hypertension/Proteinuria ND
HSP90 inhibitors NR
NR: not reported PARP inhibitors NR
ND: no data available IGF1R inhibitors NR
TMA: thrombotic PI3-kinase inhibitors NR
microangiopathy
130
these molecules, mainly with regards to agents that are
classed as antiangiogenics. Unfortunately many of the so-
called targeted agents not only affect markers that are
expressed in tumor cells but also those expressed in normal
tissues, specifically in the kidney. In a recent analysis of
kinase inhibitors, Karaman et al. [80] reported a wide
diversity of interactive patterns which could explain the
occurrence of renal adverse events.
Most of the targets modulated by anti-cancer molecular
therapies are expressed on the normal nephron. Based on
the current published data, we can identify three different
categories of nephrotoxic agents: (1) high risk of nephrop-
athy, in terms of frequency and severity, mainly represented
by the anti-VEGF/VEGFR agents and other anti-
angiogenics, (2) intermediate risk of nephropathy, with the
c-kit inhibitors, and (3) low-risk, including anti-EGFRs.
Post marketing surveillance data in a large unselected
patient population will however allow us to evaluate
whether the risks of drug induced nephrotoxicity have been
underestimated in phase I/II/III clinical trials.
Studies exploring the mechanisms of toxicities are
limited, but in order to properly manage hypertension and
proteinuria we will require an improved understanding of
the pathogenesis of drug induced nephrotoxicities. Mecha-
nisms causing renal damage are various and class depen-
dant. Toxicities with antiangiogenics are now well
identified and have been documented with preclinical
animal models and data obtained from several renal
biopsies. Clinical investigators and medical oncologists in
general might consider performing a renal biopsy more
frequently when a nephropathy related to targeted therapies
is suspected, especially in the earlier phases of develop-
ment. Hypertension and proteinuria are the most common
side effects of antiangiogenic therapy, including VEGF and
VEGFRs inhibitors.
Renal toxicities observed after antiangiogenic treatments
do not seem to be dose-dependant or dose-cumulative. For
instance, VEGF-trap renal toxicity has been observed at a
low dose in a phase I study [81], but similar effects were
not seen at higher doses. These toxicities are usually
reversible and offer the possibility of further therapies.
However, the reintroduction of a compound of the same
class should be carefully evaluated in the absence of robust
data and greater experience.
Hypertension is a potential indirect marker of anti-
angiogenic induced renal toxicity. Increased blood pressure
during a-VEGF treatment (including bevacizumab [82],
sunitinib [83] and axitinib [84]) is associated with clinical
efficacy. The direct relationship between renal toxicity and
efficacy needs to be addressed in future clinical trials.
Finally, we have to remember that the frequency of
chronic renal insufficiency among cancer patients remains
high. Before the initiation of an anticancer treatment,
Targ Oncol (2009) 4:121–133
especially with antiangiogenics, renal function must be
assessed by calculation of creatinine clearance even when
serum creatinine is within the normal range [78].
Acknowledgements We thank the Fondation Martine Midy, Paris,
France for technical assistance in preparation of this manuscript.
Conflict of interest statement No funds were received in support of
this study, nor were any benefits received from a commercial party
related directly or indirectly to the subject of this manuscript, except
those directed solely to a research fund, foundation, educational
institution or other non-profit organization with which one or more of
the author(s) is/are associated.
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