J Nephrol
DOI 10.1007/s40620-017-0392-z
REVIEW
Cisplatin nephrotoxicity: a review of the literature
Sandhya Manohar1 · Nelson Leung1,2   
Received: 31 January 2017 / Accepted: 11 March 2017
© Italian Society of Nephrology 2017
Abstract  Cisplatin is a platinum containing drug first
approved as an antineoplastic agent in 1978. It remains an
important and effective therapy in many forms of cancer
today. Cisplatin mediates its tumorcidal effects via a num-
ber of different cytotoxic mechanisms. Although it is best
known for DNA damage, cisplatin also causes cytoplas-
mic organelle dysfunction particularly with the endoplas-
mic reticulum and mitochondria. It also activates apoptotic
pathways and inflicts cellular damage via oxidative stress
and inflammation. One of its dose limiting toxicities is its
effects on the kidney. This includes acute kidney injury
as well as tubular injury resulting in  electrolyte wasting.
Extensive research has found that cisplatin entry into a cell
is facilitated by a number of cellular transporters including
human copper transport protein 1 (Ctr1) and the organic
cation transporter 2 (OCT2) which are expressed on renal
tubular cells. The interactions between the mechanisms of
cytotoxicity and cellular transport play an important role in
the nephrotoxicity. Better understanding of these interac-
tions could one day help devise better renoprotection that
would not reduce its anti-tumor effects.
Keywords  Cisplatin · Nephrotoxicity · Cytotoxicity ·
Chemotherapy · Renal protection
* Nelson Leung
Leung.nelson@mayo.edu
1
Division of Nephrology and Hypertension, Department
of Internal Medicine, Mayo Clinic, Rochester, MN, USA
2
Division of Hematology, Department of Internal Medicine,
Mayo Clinic, Rochester, MN, USA
Introduction
The discovery of cisplatin is truly a journey of serendipity.
In 1965, Rosenberg and his colleagues noticed that when
the bacteria Escherichia coli was incubated in an ammo-
nium chloride growth medium inside a chamber with plati-
num electrodes, they exhibited an unusual growth limiting
and filamentation behavior [1]. The chemical compound
was isolated and studied for its potential tumor growth
suppression properties. Cis-diamminedichloridoplatinum
[2] or cisplatin was identified and eventually approved for
use in ovarian and testicular cancer by US Food and Drug
Administration in 1978. Interestingly, cisplatin was already
known to the world as Peyronie’s chloride which was first
synthesized in 1845 by Michele Peyrone [1].
Despite tremendous advances in the field of oncology,
cisplatin continues to be a much sought after chemothera-
peutic agent. Currently, it is used in the treatment of the fol-
lowing cancers: testicular, ovarian, bladder, head and neck,
esophageal, small and non-small cell lung, breast, cervical,
stomach, prostate cancers, Hodgkin’s and non-Hodgkin’s
lymphomas, neuroblastoma, sarcomas, multiple myeloma,
melanoma and mesothelioma. Cisplatin has been on the
market for 38 years, and yet we are still struggling with its
major side effect of nephrotoxicity. Many nephro-protective
measures have been studied. In this review, we discuss the
current knowledge available regarding cisplatin, its effects
on the kidney and consider the possibilities for future direc-
tions of research.
Mechanism of action of cisplatin
Metals are essential for many of the biological processes
in the human cell, and cisplatin is a metallic-platinum
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containing drug. It is believed to affect many signal trans-
duction pathways that eventually cause an induction of
apoptosis [3]. Many mechanisms have been found to play
a role. The best-known mechanism is its effect on DNA
synthesis and repairs; which results in cell cycle arrest.
Research has also shown that cisplatin, like most metals,
is involved in generation of reactive oxygen species (ROS),
affects the tumor-suppressor protein p53, induces apopto-
sis via the death receptor-tumor necrosis factor interaction
and intrinsic caspases, causes mitochondrial dysfunction as
well as affects the calcium signaling in the cell via stress
on the endoplasmic reticulum (ER) [3]. These are but some
of the mechanisms by which it exerts its anti-neoplastic
effects. Just as its anti-neoplastic effects, cisplatin has dif-
ferent nephrotoxic effects on different parts of the nephron.
It is known to cause tubular damage, inflammatory damage
in the interstitium as well as vascular injury [4].
Intracellular events
After cisplatin enters the tubular cell, it appears to undergo
a complex series of reactions that results in its activation to
a more potent toxin. It is unclear from the current data if all
the cytotoxic effects are mediated via the activated cisplatin
metabolites. Townsend et  al. had initially looked into this
with in vivo studies by blocking the enzymatic pathways of
g-glutamyl transpeptidase (GGT) and cysteine-S-conjugate
b-lyase and found reduced nephrotoxicity from cisplatin.
Further studies showed that the two enzymes along with
glutathione-cisplatin conjugate resulted in the formation of
a reactive thiol [5, 6] which is believed to be a more potent
nephrotoxin.
To mitigate the effects of the cisplatin’s toxic metabo-
lites, many potential targets have been evaluated. High
doses of glutathione are believed to inhibit GGT competi-
tively, and some studies have shown renoprotective action
against cisplatin, though the doses required to achieve this
were large [7, 8]. Interestingly even though the conjuga-
tion of cisplatin with glutathione results in a more potent
nephrotoxin; this conjugation may actually decrease cispl-
atin’s anti-tumor effects [9]. High intracellular glutathione
has been noted to be associated with cisplatin-resistant
tumors, and a similar effect was observed in the tumor cells
with a high expression of GGT [10, 11].
Thiol agents are used in the prevention of cisplatin-
related kidney injury. It is believed that the thiol agent may
be forming a complex with cisplatin thus preventing the
formation of a glutathione-cisplatin-conjugate [8]. Ami-
fostine is one such drug. It is also the only FDA-approved
drug to prevent cisplatin-induced nephrotoxicity in patients
with non-small cell lung cancer and advanced ovarian can-
cer [12]. Unfortunately despite being FDA approved, the
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J Nephrol
cytoprotective effect of Amifostine is not consistently dem-
onstrated, with multiple reports showing evidence of tox-
icity despite administration at optimal doses with ototoxic-
ity being more commonly reported [13, 14]. Procainamide
is also another drug that is believed to work similarly to
reduce the formation of the nephrotoxin without compro-
mising the anti-tumor effect. In fact, it is thought to com-
plex with the platinum bound to DNA and prevents disso-
ciation and enhances the anti-tumor effects. Esposito et al.
noted in their mice study that when they used a combina-
tion of an otherwise lethal dose of cisplatin with procaina-
mide, the leukemic mice had a 100% survival at day 14 as
compared to zero in those receiving cisplatin alone. They
also noted a decrease in the tubular degenerative changes in
those treated with procainamide [15, 16].
Once cisplatin enters the tubular cell, it has been noted
to exert many effects which culminate in apoptosis/necrosis
of the cell. The commonly known target is the nuclear DNA
damage but only about 1 percent of the cytosolic cisplatin
is noted in the nucleus [17]. In the last four decades, mul-
tiple cellular targets have been identified. For the ease of
understanding, these have been consolidated under 5 sec-
tions: (1) DNA damage (2) Cytoplasmic organelle dysfunc-
tion: with endoplasmic reticulum stress and mitochondrial
dysfunction (3) Apoptotic pathways both caspase-depend-
ent and death receptor-mediated (4) Oxidative Stress: with
formation of reactive oxygen species and (5) Inflammation:
mediated via tumor necrosis factor and other chemokines.
DNA damage
It is well known that cisplatin mediates its antitumor effects
from DNA damage and a similar mechanism appears to
be at play in the kidney cells. Once the cisplatin enters the
cell, its complex interactions with the cellular environment
converting it into a positively charged electrophile that has
a high affinity to DNA [18]. This results in the formation of
DNA cross links that prevents DNA synthesis and replica-
tion causing the cell to be in cell-cycle arrest mode. Inter-
estingly, the nuclear DNA may not be the only site at which
cisplatin exerts its cytotoxic effect. Dissociation enhanced
lanthanide fluoroimmunoassay studies have revealed a four
to six-fold higher proportion of cisplatin adducts to mito-
chondrial DNA as compared to nuclear DNA [19]. This is
due to higher initial binding as well as the lack of cisplatin
adducts removal by the cell.
Cytoplasmic organelle dysfunction
Evidence from recent studies reveals that the endoplasmic
reticulum (ER) and mitochondria may play a critical role
J Nephrol
in cisplatin cellular toxicity [20, 21]. Mandic et al. were the
first to show this by using enucleated tumor cells to demon-
strate other triggers of apoptotic pathways via the ER [21].
They showed an upregulation in the caspase-12 activity in
these cells. Caspase-12 is localized to the ER and is acti-
vated by any changes to the calcium homeostasis, and ER
is an essential regulator of calcium homeostasis in the cyto-
sol [21].
The other important cytosolic target of cisplatin is
believed to be the mitochondria. From an electrical charge
perspective, the positively charged cisplatin electrophile
would preferentially accumulate in the negatively charged
mitochondria. Hirama et  al. demonstrated that cisplatin-
resistant ovarian tumor cells had a lower mitochondrial
membrane potential as compared to the cisplatin sensi-
tive cells [22] thus limiting the entry of cisplatin into the
mitochondria. The cisplatin-resistant cells also had less
mitochondrial DNA damage. Mitochondrial DNA lack effi-
cient DNA repair mechanisms and are more susceptible to
damage.
Mitochondrial dysfunction results in widespread effects.
A drop in ATP synthesis forces the stressed cell to function
in a starvation mode. It causes an activation of caspase-
mediated apoptosis by the release of caspase-9 mediators.
Abnormal lipid peroxidation, hypoxic injury from cispl-
atin effect on the local vasculature and the disruption of
the ATP synthesis process results in the production of free
radicals or reactive oxygen species [23]. Mouse kidney cell
studies by Portilla have demonstrated a role of cisplatin in
inhibiting fatty acid oxidation via peroxisome proliferator
activated receptor α (PPARα) transcription downregulation
thus affecting energy synthesis [24]. The role of a PPARα
ligand was explored and was found to reduce the incidence
of acute kidney injury in mice [25].
Qian et al. showed an interesting association between the
cell sensitivity to cisplatin-induced cell death and the mito-
chondrial density of that cell. They showed this in intestinal
cells where the density of mitochondria decreases as one
moves from the duodenum to the ileum and they were able
to demonstrate a difference in the cell-specific sensitivity
to cisplatin with greater cell death occurring in the duode-
num as compared to ileum [26]. This is interesting as the
proximal tubule cells are known to have the highest density
of mitochondria as compared to the rest of the tubules, and
this is where cisplatin-induced damage is commonly noted.
Apoptosis
Cisplatin activates not just the intrinsic apoptotic path-
ways (via the ER or mitochondrial dysfunction) but also
the extrinsic death receptor pathway by tumor necrosis fac-
tor alpha (TNFα) production. DNA damage can result in
activation of p53 which can trigger apoptosis. ROS, which
forms either from DNA damage, mitochondrial dysfunc-
tion or inflammatory triggers, can also trigger apoptosis.
The many mechanisms through which cisplatin can exert
its influence on the cell and cause cell death is precisely
the reason that makes it an indispensable anti-cancer drug
and a challenge to protect the healthy cells from innocent
bystander death. A simplified summary of this has been
depicted in Fig. 1.
The role of autophagy has also been explored, and its
protective role has been demonstrated by Periyasamy-
Thandavan et  al. in cultured proximal tubular cells [27].
They noted autophagosomes develop within hours of cis-
platin administration with p53 possibly playing a role in
the signaling process. When autophagy was pharmaco-
logically blocked, there was accelerated apoptotic process
noted [27]. Anti-apoptotic measures have been evaluated
for renoprotective strategy. P53 inhibition in  vitro studies
like siRNA targeted at p53 have shown a reduction in kid-
ney injury but considering the vast array of cell protective
functions of p53, extensive in vivo studies will be needed
before human use. A major theoretical concern as Fraser
et al. demonstrated is the possibility of affecting cisplatin’s
anti-tumor activity by the p53 inhibition [28].
Oxidative stress
Oxidative stress is the imbalance between the free radi-
cal production and consumption. Three mechanisms have
been proposed that result in the production of ROS [29].
First, its interaction with glutathione during its activation
to a more potent nephrotoxin depletes the cell of a potent
antioxidant molecule like glutathione. Second, it affects the
mitochondrial respiratory chain resulting in the production
of ROS and the third is via cytochrome p450 effect in the
microsomes [29]. The downstream target of the ROS is not
clear. It appears to act via multiple mechanisms as would
be expected based on their highly reactive nature. Admin-
istration of an antioxidant dimethylthiourea (DMTU) abol-
ished p38 activation in one study [30] and p53 activation in
another [31].
Supplementation with antioxidants has hence been con-
sidered for nephroprotection as well. Both natural and syn-
thetic formulations have been evaluated. Vitamin C, vita-
min E, selenium, alpha lipoic acid, ubiquinone and other
enzymatic antioxidants like DMTU are just to name a few.
Most of the beneficial effects were noted in the in  vitro
and in vivo mice studies [29]. An attempt to replicate this
in humans by Weijl et  al. with vitamin C, vitamin E, and
selenium supplementation though showed no benefit from
the antioxidant micronutrient supplementation [32]. Mag-
nesium is another supplement that has been shown to be
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 J Nephrol

Cisplan
Ctr1
OCT2

Entry into the cell

GGT
cysteine-S-conjugate b-lyase

Acvaon in the cell

Death receptor
pathway
Endoplasmic
Reculum
DAMPs DNA Damage pathway
P53 acvaon
Acvaon Mitochondrial
Of TLR4 ROS pathway
NF-KB
pathway Caspase 8
Cytochrome c AIF Caspase 12 acvaon
Cytokines/Chemokines
acvaon
TNFα
Caspase 9 Caspase
acvaon independent

Inflammaon Apoptosis

Fig. 1  Summary of the major pathways of Cisplatin induced tubu- molecular pattern molecules, TLR toll-like receptor, TNFα tumor
lar cell injury. Ctr1 copper transporter 1, OCT2 organic cation trans- necrosis factor alpha, ROS reactive oxygen species, AIF apoptosis
porter 2, GGT g-glutamyl transpeptidase, DAMPs damage-associated inducing factor

helpful in reducing cisplatin related toxicity. Solanki et al.
have noted in their mice studies that a deficiency of magne-
sium amplifies markers of renal damage which is promptly
reversed by supplementation with magnesium. It is a cofac-
tor for many of the signaling pathways in the cell and its
role in regulation of oxidative stress, apoptosis and cispl-
atin efflux is well demonstrated in their studies without loss
of anti-tumor activity [33].
Inflammation
Cisplatin has also been found to have an inflamma-
tory effect on the kidneys. Cisplatin is believed to cause
intracellularly injury resulting in the release of damage-
associated molecular pattern molecules (DAMPS) also
called “alarmins”. DAMPs are endogenous molecules
that are produced during tissue injury. DAMPs are known
to act on Toll-like receptors (TLRs). TLRS are a family
of receptors that have a pattern recognition feature and
play a vital role in the immune system. Via multiple
pathways, TLRs in turn cause the release of chemokines
and other cytokines like TNFα to be released attracting
the inflammatory cells [34, 35]. This was demonstrated
by Zhang et al. using TLR 4 knockout (KO) mice. They
showed that the levels of cytokines like TNFα were sig-
nificantly higher in the cisplatin-treated wild-type mice
as compared to the cisplatin-treated TLR4 KO mice. The
former also had more renal damage as compared to the
latter suggesting that DAMPS-TLR4 TNFα pathway may
be contributing to the renal injury [36] (Fig.  1). IL-10
may have a protective role in decreasing the inflammation
[37].
In order to mitigate these effects of inflammation cas-
cade, intervention at different stages has been evaluated.
Salicylates have a well know anti-inflammatory action.
Studies found cisplatin-exposed mice treated with salicy-
late had a significant reduction of TNFα protein levels in
their serum [38]. Considering higher doses are needed
for the anti-inflammatory effect and its usage is limited in

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patients with renal dysfunction, the use of salicylate may be
a challenge.
The production of TNFα after cisplatin administration
seems to be dependent on a nuclear factor-kappa B (NF-
κB) pathway and TNFα, in turn, needs to act on endothe-
lial adhesion molecules (ICAM-1) to attract inflammatory
cells. Alpha lipoic acid has an anti-inflammatory effect
by affecting the expression of ICAM-1 and suppressing
the NF-κB signaling pathway. This was demonstrated by
Kang et al. [39] in their study in 2009. Similarly, the role
of TNFα antagonism, TLR4 antagonism, and p38 inhibi-
tors has been explored [30, 36, 40]. A major concern is that
by controlling the inflammation, there would be mitigation
of the long-term consequences of fibrosis. This is yet to be
explored.
Cellular uptake
Cisplatin is a drug that is not only freely filtered but also
actively secreted into the urine. Movement of cisplatin
through the renal tubular cells is from a basolateral to api-
cal direction. Two primary transporters are now known
to be involved in transporting cisplatin into the tubular
cells, the human copper transport protein 1 (Ctr1) and the
organic cation transporter 2 (OCT2). Ctr1 is a protein that
is expressed in multiple organ sites in the body and its pri-
mary role, as the name implies, is in copper transport but
only in the last decade have we have found evidence for its
role in the transport of cisplatin [41]. In animal models,
Pabla et al. found high expression of Ctr1 in both proximal
and distal tubules mostly localized on the basolateral side
[42]. The KO Ctr1 mice also showed a decrease in cisplatin
uptake resulting in a decrease in tubular cell apoptosis at
low dose exposure as well as cell necrosis in high dose cis-
platin exposure.
The presence of excess copper degrades and down-
regulates the Ctr1 expression. A similar effect is induced
by cisplatin [41]. This has led to the discovery that certain
cisplatin-resistant tumors have low expressions of Ctr1
[43]. It has also been noted that certain resistant tumors
have high expression of copper effluxors on the cancer cell
membrane. Recently, it has been pointed out that the use
of copper chelator may help improve the sensitivity of the
previously cisplatin-resistant tumors [44]. So consider-
ing the crucial role Ctr1 plays in the entry of cisplatin into
the tumor cell, concern has been raised that targeting this
transporter for a renoprotective strategy may affect the anti-
tumor effects of the drug.
Work has also been done looking at the role of secre-
tion of cisplatin from the tubules into the lumen and its role
in causing tubular injury. In rats, probenecid was found to
be capable of blocking cisplatin tubular secretion into the
urine via the organic anion transporter 1 (OAT1) [45, 46].
This led to a phase I trial was performed by Jacobs et al. by
infusing probenecid before and for 24 h after the adminis-
tration of cisplatin [47]. The authors found no significant
nephrotoxicity in their probenecid treated patients despite
dose escalation of cisplatin. Unfortunately, patients devel-
oped ototoxicity followed by neurotoxicity at higher doses.
The OCT2 belongs to the SLC22 family of transporters.
It is expressed in the intestine, kidney, liver and brain. In the
kidney, it also has a high expression on the basolateral side
of the proximal convoluted tubule [48]. These transporters
are poly-specific uniporters that can operate in either direc-
tion, but they preferentially mediate the transport of the cat-
ions into the cell at normal membrane potential [49]. OCT2
KO mice studies by Filipsi et  al. demonstrated protection
from cisplatin-mediated renal tubular damage [50]. Similar
studies were performed by Ciarimboli et al. using a double
KO mice model, where both OCT 1 and 2 receptors were
knocked out [51, 52]. These KO mice had no signs of oto-
toxicity and only mild nephrotoxicity. There was a substan-
tial reduction (about four-fold) in the quantity of cisplatin
that accumulated in the kidney [51]. Interestingly, the less
nephrotoxic platinum compound carboplatin does not seem
to be transported via OCT2 [52]. Oxaliplatin is transported
by OCT2 but it is rapidly transported out of the renal tubu-
lar cell by multidrug and toxin extrusion (MATE/SLC47A)
thus reducing its nephrotoxicity [53]. Finally, procainamide
is transported by OCT2 and has been shown to interfere
with the transport of other organic cations. However, pro-
cainamide is mainly transported by OCT2A and its interfer-
ence with cisplatin transport remains uninvestigated [54].
Many in vitro and in vivo studies have been done look-
ing into the role of cimetidine in blocking the renal effects
of cisplatin [51, 52]. Sleijfer et  al. had conducted a small
case-control study wherein verapamil and cimetidine were
administered to a group of patients [55]. Verapamil was
given mainly for its vasodilatory effects in the kidney. They
noted that the patients that received the two-drug combina-
tion did not have a significant drop in the glomerular filtra-
tion rate (GFR) as compared to those that received cisplatin
alone.
Clinical presentation of cisplatin nephrotoxicity
Nephrotoxicity with cisplatin does not refer to renal failure
alone. In fact, acute kidney injury is seen in just approxi-
mately 20–30% of the patients [56–58]. Before the era of
hydration and diuresis, the incidence was noted in almost
100% of the patients [56, 58]. The more common kidney
manifestation is hypomagnesemia, the prevalence is esti-
mated to be between 40 and 100% [59–61]. Other mani-
festations Fanconi-like syndrome [62–64], distal renal
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 J Nephrol

tubular acidosis [65], renal concentrating defect [66, 67]
and thrombotic microangiopathy [68] are among a few of
the well-known complications (Table 1).
Risk factors for cisplatin nephrotoxicity
It is well known that cisplatin kidney injury is dose-dura-
tion-frequency dependent [58, 75]. Higher peak plasma
concentrations from higher doses per treatment result in
greater injury [76, 77]. A higher cumulative dose has also
been shown to increase risk for future kidney injury [78].
There are also certain patient-related factors that make
them more susceptible to kidney damage. Ignard–Bagnis
et al. demonstrated that older patients, patients with signifi-
cant comorbid illness and baseline poor functional status
were at a higher risk [23]. Additionally, patients with lower
albumin are also presumed to have a higher unbound frac-
tion of cisplatin resulting in greater peak plasma concen-
trations [75]. Patients with preexisting kidney disease and
concurrent use of nephrotoxic medications (like non-steroi-
dal anti-inflammatory drugs NSAIDS, iodinated contrast)
are also at a greater risk [23, 75] (Table 2).
Pathological changes in cisplatin nephrotoxicity
Patients with cisplatin-mediated kidney injury do not
need a routine kidney biopsy unless the clinical situa-
tion demands a clarification that can alter the patient’s
Table 2  Risk factors for Cisplatin induced nephrotoxicity
 Patient factors
 Older age
 Low functional status
 Malnourished
 Dehydration
 Chronic comorbid illness —diabetes mellitus, Liver dysfunction
 Preexisting chronic kidney disease
 Concurrent nephrotoxic drug use (iodinated contrast, NSAIDS,
gemcitabine)
 Electrolyte disturbances (low magnesium)
 Alcohol ingestion
Cisplatin drug related factors
 High dose per treatment (greater 50 mg/m2)
 Frequency of administration
 Cumulative dose
 Hydration with cisplatin administration
NSAIDS non-steroidal anti-inflammatory drugs
management. Based on the pathophysiology, most of the
damage is expected to be in the tubulo-interstitial com-
partment with minimal glomerular changes which has
been confirmed in both rat and human autopsy studies
[79, 80]. There appeared to be a gradual involvement of
the tubules with a predominant proximal tubular compo-
nent. It is not known to cause interstitial nephritis [80].
In patients who have had chronic use of cisplatin, it has
been noted to cause significant tubular atrophy and inter-
stitial fibrosis with relative glomerular sparing [81].

Table 1  Some common Clinical manifestations of Cisplatin induced Nephrotoxicity

Clinical manifestation Mechanism References

Acute kidney injury Dose and frequency dependent [58, 64]

Hypomagnesaemia Possibly related to distal tubular injury affecting magnesium [69, 70]
reabsorption
Magnesium deficiency may also exacerbate the renal toxicity of
cisplatin
Fanconi-like syndrome From proximal tubular injury [71]
Distal renal tubular acidosis From tubular injury [65]
Renal concentrating defect Affects proximal tubular sodium reabsorption [72, 73]
Occurs in 2 phases Decreases aquaporin expression in the distal tubule
 a. Early phase (within 24–48 h) and resolve spontaneously. Presumed also due to damage to loop of Henle especially Na-K-
Presumed prostaglandin mediated. Prevented by vasopressin 2Cl transporter and affecting countercurrent regulatory system
and aspirin
 b. Second phase (72–96 h) with a decrease in GFR. Associated
with decrease in medullary tonicity
Thrombotic microangiopathy Unclear but has been seen in conjunction with bleomycin or [68]
gemcitabine use
cisplatin-induced glucose intolerance Rat studies show a relative insulin deficiency state as well as an [74]
impaired glucagon response

GFR glomerular filtration rate; Na-K-2Cl sodium–potassium-2 chloride

13
 Table 3  Strategies for preventing or reducing nephrotoxicity from Cisplatin that have been explored
Level of action Drug Mechanism of action Comments
J Nephrol

Glomerular filtration Micellar/liposomal cisplatin Incorporating cisplatin into polymeric micelles which can Mice models showed a decrease in nephrotoxicity but
possibly reduce its filtration into urine caused hepatic dysfunction
Cell entry OCT2 Inhibitors: Cimetidine, metformin Reduces the entry of cisplatin into the tubular cells as a Cimetidine appears to be promising but paucity of human
competitive substrate for OCT2 receptor studies
Ctr1 inhibitors: copper Reduces the entry of cisplatin into the tubular cells as a Concern for affecting the anti-tumor effect of cisplatin has
competitive substrate for Ctr1 receptor been raised
Cell activation GGT inhibitors: acivicin Reduces activation of cisplatin-Glutathione conjugate into Acivicin is the drug used for GGT inhibition and has poten-
a more reactive and nephrotoxic thiol compound tial anti-neoplastic activity as well that is being explored
Glutathione transferase inhibitors: ketoprofen Reduces activation of cisplatin-glutathione conjugate into The mice model used ketoprofen as the inhibitor which is
a more reactive and nephrotoxic thiol compound a non-steroidal anti-inflammatory drug that can cause
kidney injury on its own
High dose glutathione Competitively inhibits GGT and so preventing the metabo- High doses of glutathione are needed
lism of glutathione-cisplatin-conjugate into a more
potent nephrotoxin
Thiol agents: amifostine, procainamide Complexes with cisplatin and preventing the formation of Amifostine is the only FDA approved drug for reducing
a glutathione-cisplatin-conjugate and its further metabo- nephrotoxicity in ovarian cancer and non-small cell lung
lism into a more potent nephrotoxin cancer
Inflammatory response TNFα antagonists Prevent the release of cytokine/chemokine that propagate –
TLR4 antagonists the inflammatory process
p38 inhibitors
JNK inhibitors Cisplatin causes reactive oxygen species which stimulates The selective inhibitor reduced not only renal inflammation
the JNK pathway causing the release of pro-inflamma- but also apoptotic cell death
tory cytokines
Salicylates Reduces the production of TNF-alpha High doses are needed for anti-inflammatory action which
may be the limiting factor in these that have a propensity
for renal dysfunction
PPAR-α ligands [25, 84] Reduced the expression of cytokine/chemokines by cispl- Fibrates are PPAR α ligands used in dyslipidemia and one
atin injured cell likely via inhibition of NF-κB pathway could consider its role in patients that also have concur-
Also has a role in mitochondrial fatty acid oxidation and rent lipid disorder
energy synthesis which is affected by cisplatin
Alpha lipoic acid Reduces the expression of ICAM-1 on endothelial cells Currently used as an adjunct antioxidant effect in patients
and suppresses the NF-κ B signaling pathway for TNFα with painful neuropathy
production
IL-10 [85] Known anti-inflammatory cytokine IL-10 was found to be protective from cisplatin associated
injury

13


Table 3  (continued)
Level of action Drug Mechanism of action Comments

13
Oxidative stress Natural antioxidants [29] In vitro and in vivo studies have shown a reduction in the Human studies have not shown any benefit
 Selenium ROS generation as well as reduction in the renal injury
 Magnesium
 Vitamin E
 Vitamin C
 Naringenin (citrus fruits)
 Lycopene (tomatoes)
 Spirulin (algae)
 Garlic
Among others
Enzymatic anti-oxidants [29]
 Superoxide dismutase
 N-acetyl cysteine
 Dimethylthiourea (DMTU)
Among others
PARP inhibitors Inhibition of PARP activation was shown to downstream Enalapril is an inhibitor of PARP activation and was studied
effects of reduction in oxidative stress pathways of with reduction in renal ­injurya
MAPKs/TNFα/NF-κB mediated inflammation and
apoptosis
Anti-apoptosis P53 inhibitors P53 is a major mediator in cisplatin induced apoptosis P53 suppression was shown by Fraser et al. to promote
and the trigger is believed to be DNA damage oxidative cisplatin resistance in ovarian cancer cell lines
stress
P21 agonist/CDK2 inhibitors P21 is a cell cycle inhibitor which upregulates on exposure
to cisplatin and by upregulating it tubule cell ­protectionb

OCT2 organic cation transporter 2, Ctr1 copper transporter 1, GGT g-glutamyl transpeptidase, TNFα Tumor necrosis factor- alpha, TLR = Toll-like receptor, JNK c-jun N-terminal kinase,
PPAR-α peroxisome proliferator activated receptor alpha, NF-κB nuclear factor κB, IL interleukin, PARP poly ADP ribose polymerase, MAPK mitogen-activated protein kinases
a
 Rani et al. [86]
b
 Price et al [87]
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J Nephrol
Long‑term kidney consequences in cisplatin
nephrotoxicity
In the last few decades, significant effects of chronic kid-
ney disease (CKD) on the overall morbidity and mortality
of these patients have been noted. To add to this, more
patients are surviving longer after cancer treatment and
in their older age are dealing with the consequences of
the chronic kidney disease that they acquired from their
intense therapy earlier in their life. Dekker et  al. looked
at over 800 childhood cancer survivors with a median
follow-up of 18 years noted that one of the risk factors for
development of CKD was high dose cisplatin use [82].
Interestingly a Cochrane Systematic review showed a
trend toward cisplatin-based chemotherapy and chronic
kidney disease but did not reach statistical significance.
They did note a significant association with proteinuria.
Significant heterogeneity of the data with limited follow-
up made it difficult to come to a definite conclusion [83].
Experimental strategies to prevent cisplatin
nephrotoxicity
Based on the pathophysiology discussion earlier, there
are many potential options for intervention and preven-
tion of cisplatin-induced kidney injury. As previously
mentioned, many have been tried. The biggest challenge
is to protect the kidney while not reducing its tumor-
cidal effects. The best-known and most commonly used
strategy is that of hydration and forced diuresis with diu-
retics or mannitol which will not be further discussed
here. Table  3 lists a summary of some of the strategies
that have been explored and have a potential for future
research.
Future direction
In summary, the last few years has given us new insights
regarding the various mechanisms at play in causing
cisplatin-induced nephrotoxicity. The complexity of cis-
platin’s cytotoxic actions explains why nephrotoxicity
continues to remains a major challenge. Uncovering the
pathways will trigger research looking at focused reno-
protective strategies, and hopefully, human clinical trials
will soon follow.
Compliance with ethical standards  toxicity and pharmacokinetics. Laryngoscope 114(9):1660–1667
Funding None.
Conflict of interest  We do not have any financial or non-financial
potential conflicts of interest.
Ethical approval  This article does not contain any studies with
human participants performed by any of the authors.
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