17. Gross O, Perin L, Deltas C. Alport syndrome from bench to bedside: the || 26. Teasdale TW, Sorensen MH.

26. Teasdale TW, Sorensen MH. Hearing loss in relation to educational attain-
potential of current treatment beyond RAAS-blockade and the horizon of ||
future therapies. Nephrol Dial Transplant 2014; 29: iv124–iv130 ||
18. Gross O, Licht C, Anders HJ et al. Early angiotensin converting enzyme ||
inhibition in Alport syndrome delays renal failure and improves life expect-
||
||
ancy. Kidney Int 2012; 81: 494–501 ||
19. Temme J, Peters F, Lange K et al. Incidence of renal failure and ||
nephroprotection by RAAS-inhibition in heterozygous carriers of X- ||
chromosomal and autosomal-recessive Alport-mutations. Kidney Int 2012;
||
||
81: 779–783 ||
20. Kashtan CE, Ding J, Gregory M et al. Clinical Practice Guidelines for the ||
Treatment of Alport Syndrome. A Statement of the Alport Syndrome ||
Research Collaborative. Ped Nephrol 2013; 28: 5–11
||
||
21. Savige J, Gregory M, Gross O et al. Expert Guidelines for the management
of Alport syndrome and TBMN. J Am Soc Nephrol 2013; 24: 364–375
22. Voskarides K, Arsali M, Athanasiou Y et al. Evidence that NPHS2-R229Q
predisposes to proteinuria and renal failure in familial hematuria. Pediatr
Nephrol 2012; 27: 675–679
23. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work
Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation
ment and cognitive abilities: a population study. Int J Audiol 2007; 46:
172–175
27. Fellinger J, Holzinger D, Sattel H et al. Correlates of mental health disorders
among children with hearing impairments. Dev Med Child Neurol 2009; 51:
635–641
28. Cosgrove D, Samuelson G, Meehan DT et al. Ultrastructural, physiological,
and molecular defects in the inner ear of a gene-knockout mouse model of
autosomal Alport syndrome. Hearing Res 1998; 121: 84–98
29. Harvey SJ, Mount R, Sado Y et al. The inner ear of dogs with X-linked neph-
ritis provides clues to the pathogenesis of hearing loss in X-linked Alport
syndrome. Am J Pathol 2001; 159: 1097–1104
30. Zehnder AF, Adams JC, Santi PA et al. Distribution of type IV collagen in
|| the cochlea in Alport syndrome. Arch Otolaryngol Head Neck Surg 2005;
|| 131: 1007–1013
|| 31. Meyer zum Gottesberge AM, Gross O, Becker-Lendzian U et al. Inner ear
||
|| defects and hearing loss in mice lacking the collagen receptor DDR1. Lab
|| Invest 2008; 88: 27–37
|| 32. Temme J, Kramer A, Jager KJ et al. Outcomes of male patients with Alport
|| syndrome undergoing renal replacement therapy. Clin J Am Soc Nephrol
||

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

and Management of Chronic Kidney Disease. Kidney Int Suppl 2013; 3: || 2012; 7: 1969–1976
1–150 || 33. Brainwood D, Kashtan C, Gubler MC et al. Targets of alloantibodies in
24. Jais JP, Knebelmann B, Giatras I et al. X-linked Alport syndrome: natural || Alport anti-glomerular basement membrane disease after renal transplanta-
history and genotype-phenotype correlations in girls and women belonging
|| tion. Kidney Int 1998; 53: 762–766
||
to 195 families: a ‘European Community Alport Syndrome Concerted || 34. Mallett A, Tang W, Clayton PA et al. End-stage kidney disease due to
Action’ study. J Am Soc Nephrol 2003; 14: 2603–2610 || Alport syndrome: outcomes in 296 consecutive Australia and New Zealand
25. Woodcock K, Pole JD. Educational attainment, labour force status and || Dialysis and Transplant Registry cases. Nephrol Dial Transplant 2014; 29:
injury: a comparison of Canadians with and without deafness and hearing
|| 2277–2286
||
loss. Int J Rehabil Res 2008; 31: 297–304 ||
|| Received: 13.2.2016; Editorial decision: 29.3.2016
||
|

Nephrol Dial Transplant (2017) 32: 924–936

doi: 10.1093/ndt/gfw338
Advance Access publication 6 October 2016

Nephrotoxicity of anticancer treatment

Jolanta Małyszko1, Klaudia Kozłowska1, Leszek Kozłowski2 and Jacek Małyszko3
1
2nd Department of Nephrology and Hypertension with Dialysis Unit, Medical University in Bialystok, 2Department of Oncological Surgery,
Ministry of Interior Affairs Hospital, Bialystok, Poland and 31st Department of Nephrology and Transplantology with Dialysis Unit, Medical
University in Bialystok, Białystok, Poland

Correspondence and offprint requests to: Jolanta Małyszko; E-mail: jolmal@poczta.onet.pl

|| with high-grade lymphomas and acute lymphoblastic leukae-

ABSTRACT || mia. Chemotherapeutic agents can affect the glomerulus,
|| tubules, interstitium and renal microvasculature, with clinical
Severe adverse systemic drug events occur commonly as a result
||
|| manifestations that range from asymptomatic elevation of
of treatment of cancer patients. Nephrotoxicity of chemothera- || serum creatinine to acute renal failure requiring dialysis. Some
peutic agents remains a significant complication limiting the
||
|| factors such as intravascular volume depletion, as well as con-
efficacy of the treatment. A variety of renal disease and electro- || comitant use of other drugs or radiographic ionic contrast
||
lyte disorders can result from the drugs that are used to treat || media, can potentiate or contribute to the nephrotoxicity.
malignant disease. The kidneys are a major elimination pathway ||
|| Cytotoxic agents can cause nephrotoxicity by a variety of mech-
for many antineoplastic drugs and their metabolites. Tumour || anisms. The most nephrotoxic chemotherapeutic drug is cispla-
lysis syndrome, an emergency in haematooncology, occurs ||
|| tin, which is often associated with acute kidney injury. Many
most often after the initiation of cytotoxic therapy in patients | other drugs such as alkylating agents, antimetabolites, vascular

C The Author 2016. Published by Oxford University Press

V 924
on behalf of ERA-EDTA. All rights reserved.
endothelial growth factor pathway inhibitors and epidermal ||
||
growth factor receptor pathway inhibitors may have toxic effects ||
on the kidneys. The aim of this review is to discuss the issue of ||
||
nephrotoxicity associated with chemotherapy. In routine clini- ||
cal practice, monitoring of kidney function is mandatory in ||
||
order to identify nephrotoxicity early, allowing dosage adjust- ||
ments or withdrawal of the offending drug. ||
||
Keywords: cancer, chemotherapy, electrolytes, nephrotoxicity,
||
||
targeted therapies ||
||
||
|| FIGURE 1: Types of kidney injury.
INTRODUCTION ||
||
||
Rapid advances in cancer treatment have changed the landscape ||
in oncology for both patients and physicians. Patients are deriv-
||
||
ing significant benefits due to decreased tumour progression ||
||

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

and increased survival, as well as less severe adverse systemic ||
drug events. However, the Janus face of the chemotherapeutic ||
agents is nephrotoxicity, which remains a significant complica-
||
||
tion limiting the efficacy of the treatment. Therefore, the early ||
diagnosis and prompt treatment of this complication is essential
||
||
in daily practice to ensure the best possible results. ||
||
A variety of renal disease and electrolyte disorders can result ||
from the drugs that are used to treat malignant disease [1–6]. ||
||
The kidneys are a major elimination pathway for many antineo- ||
|| FIGURE 2: Renal effects of targeted therapies.
plastic drugs and their metabolites. There are two principal path-
||
ways for drug excretion by the kidney: glomerular filtration and |
tubular secretion. Glomerular filtration plays a major role with ||| secondary to underlying tumour. Last, but not least, there may
|| be intrinsic renal disease that is idiopathic, related to other
non-protein-bound small molecules (i.e. of a size that can pass ||
|| comorbidities, i.e. diabetes, hypertension, chronic heart failure
through the glomerular capillary wall). Such molecules cannot
|| or to the malignancy itself. Thus, kidney vulnerability to chemo-
be filtered if they are protein-bound in the circulation; these ||
|| therapy may be due to kidney-related tumour effects, tumour-
drugs, if they are renally excreted, enter the urine by secretion in
|| specific factors, kidney drug handling and innate drug toxicity
the proximal tubule. Chemotherapeutic agents can affect the glo- ||
|| [1–6].
merulus, tubules, interstitium or the renal microvasculature,
||
with clinical manifestations that range from an asymptomatic ||
elevation of serum creatinine to acute renal failure requiring dial- || TUMOUR LYSIS SYNDROME
||
ysis [1–6] (Figure 1). So chemotherapy-induced kidney disease ||
could be categorized as follows: acute kidney injury (AKI) due to || Tumour lysis syndrome is an emergency in haematooncology.
||
thrombotic microangiopathy (TMA), toxic acute tubular || It occurs most often after the initiation of cytotoxic therapy in
necrosis, crystal nephropathy, proteinuria/nephrotic syndrome || patients with high-grade lymphomas (particularly the Burkitt
||
due to TMA, focal segmental glomerulosclerosis (FSGS), mini- || subtype) and acute lymphoblastic leukaemia [7]. It may also
mal change disease, membranous nephropathy; tubulopathies || occur spontaneously and with other tumour types that have a
||
due to electrolyte, acid-base and divalent disorders; and chronic || high proliferative rate, large tumour burden or high sensitivity
kidney disease (CKD) due to glomerulopathies or interstitial || to cytotoxic therapy.
||
nephritis [1–6]. Renal effects of targeted therapies are shown in || Other risk factors include: pretreatment hyperuricaemia
Figure 2. || (serum uric acid >7.5 mg/dL) or hyperphosphataemia, a pre-
||
There are several factors that could potentiate renal dysfunc- || existing nephropathy or exposure to nephrotoxins, oliguria
tion and contribute to the nephrotoxic potential of antineoplas- || and/or acidic urine, dehydration, volume depletion or inad-
||
tic drugs, i.e. intravascular volume depletion, either due to || equate hydration during treatment [8, 9]. Effective targeted
external losses or fluid sequestration (as in ascites or oedema). || anticancer drugs used in haematology such as venetoclax (ABT-
||
This condition appears to be the most common factor contribu- || 199), an investigational B-cell lymphoma 2 (BCL2) inhibitor,
ting to the nephrotoxic potential of antineoplastic drugs. In
|| obinutuzumab (anti-CD20 monoclonal antibody), dinaciclib
||
addition, the concomitant use of other nephrotoxic drugs [e.g. || (cyclin-dependent kinase inhibitor) and alvocidib (flavopiridol,
aminoglycoside antibiotics, nonsteroidal antiinflammatory
|| cyclin-dependent kinase inhibitor) are associated with an
||
drugs (NSAID)] may also enhance a risk of kidney injury in || increase in the frequency and severity of tumour lysis syndrome
patients with or without pre-existing renal dysfunction. ||| [9]. Massive tumour cell lysis leads to release of large amounts
Moreover, there may be concomitant urinary tract obstruction
|| of potassium, phosphate and nucleic acids into the systemic
||

Chemotherapy-associated nephrotoxicity 925

circulation [7, 8]. Nucleic acids are catabolized into uric acid ||
causing hyperuricaemia, which in turn can result in the precipi- ||
tation of uric acid in the renal tubules. In addition, hyperphos-
||
||
phataemia may lead to calcium phosphate deposition in the ||
renal tubules. This can clinically manifest as AKI of post-renal
||
||
origin (obstructive nephropathy). High levels of both uric acid ||
and phosphate increase the severity of acute kidney injury
||
||
because uric acid precipitates readily in the presence of calcium ||
||
phosphate crystals, and calcium phosphate precipitates readily ||
in the presence of uric acid crystals. Moreover, hyperuricaemia ||
||
can also induce renal vasoconstriction, impaired autoregulation, ||
decreased renal blood flow and inflammation, also resulting in ||
||
AKI of renal origin [7, 8]. ||
||
||
||
CYTOTOXIC DRUGS ||
||
||
Cytotoxic agents can cause nephrotoxicity by a variety of mech- ||
||
anisms. While many drugs induce a fall in the glomerular filtra- ||
tion rate (GFR) that is dose-related and predictable, others are ||
||
associated with a more protracted decline in renal function, ||
which is often irreversible.
Platinum derivatives
Cisplatin [Cis-diamminedichloroplatinum(II)] is the most
nephrotoxic chemotherapeutic drug, discovered over four deca-
des ago. Nephrotoxicity is the major side effect that limits the
dose of cisplatin that can be safely administered, and it is a clini-
cal problem in cancer patients who receive cisplatin combina-
tion chemotherapy. On the other hand, this is one of the most
commonly used antineoplastic drugs. Multiple mechanisms
including tubular epithelial cell toxicity, vasoconstriction in the
renal microvasculature and proinflammatory effects contribute
to renal dysfunction following exposure to cisplatin. The mech-
anism of nephrotoxicity is associated with a chloride ion at the
cis position of the drug. Basolateral drug transporters play a role
in cisplatin uptake. Changes in expression of proximal tubule
organic cation transporter-2 (OCT2) have been shown to medi-
ate the accumulation of cisplatin in proximal tubular epithelial
cells, suggesting a key role for OCT2 in the development of
cisplatin-mediated nephrotoxicity [10]. More than 50% of the
drug is excreted in the urine in the first 24 h following cisplatin
administration, and the concentration of platinum achieved in
the renal cortex is several-fold greater than that in plasma and
other organs [11]. Cisplatin primarily injures the S3 segment of
the proximal tubule, causing a decrease in the GFR [12]. It is
manifest by both necrosis and apoptosis, even though non-
proliferating cells are generally less sensitive to the toxicity of
agents that damage DNA [13]. Moreover, decreased renal blood
flow due to vasoconstriction is observed soon after cisplatin
injection [14]. The kidney response to cisplatin also includes
increased expression of proinflammatory cytokines, such as
tumour necrosis factor alpha (TNF-a), interleukin-6 (IL-6),
interferon-gamma (IFN-gamma) and caspases, which promote
the differentiation, maturation and activation of neutrophils, T
cells, cyclin-dependent kinases, mitogen-activated protein kin-
ase (MAPK) activation, p53 signalling and other components of
the cellular inflammatory response [15, 16]. Thus, cellular
926
injury is due to inflammation and oxidative stress. Tubulopathy
following cisplatin administration may be due to its enhanced
renal uptake by organic transporters [17]. Cisplatin also causes
reduced expression and function of sodium-dependent glucose
and amino acid transporters [18], reduced expression and func-
tion of magnesium and water transporters [10, 11], metabolism
of cisplatin to glutathione and cysteinyl-glycine conjugates [19],
and the generation of reactive oxygen species [20]. This mecha-
nism of action also explains the features of Fanconi-like syn-
drome following cisplatin therapy. Cisplatin nephrotoxicity also
appears to be mediated by the organic cation transporter
(hOCT2) [21]. In an experimental mouse model of cisplatin-
induced CKD, Torres et al. [22] using quantitative analysis
revealed that a major long-term cisplatin effect was a reduction
in the number of cuboidal cells of the glomerular capsule, and
glomerulotubular disconnection; however, connection rem-
nants between damaged tubules and atubular glomeruli
Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021
persisted. These reductions in normal glomerular capsules cor-
responded to reductions in GFR. In the clinical setting, the most
common and important manifestation of cisplatin nephrotoxic-
ity is AKI, which can be progressive and even irreversible. Other
|| renal manifestations include hypomagnesaemia, salt wasting, a
||
|| Fanconi-like syndrome and anaemia. Hypomagnesaemia is due
|| to urinary magnesium wasting and on the other hand, hypo-
||
|| magnesaemia may exacerbate cisplatin toxicity [23]. Prevalence
|| of cisplatin nephrotoxicity depends upon the dose and fre-
||
|| quency of drug administration as well as previous exposure to
|| cisplatin, pre-existing kidney damage, and the concomitant use
||
|| of other nephrotoxic agents such as aminoglycosides, NSAID or
|| iodinated contrast media. When cisplatin is administered with
||
|| bleomycin or gemcitabine, it may cause TMA mainly due to
|| direct endothelial injury with secondary platelet activation [24].
||
|| In most cases of AKI caused by cisplatin, the urine output
|| remains above 1000 mL per day due to the induction of a con-
||
|| centrating defect, except in cases with advanced AKI. Recently,
|| in the largest study of adult patients with cancer (n ¼ 821) who
||
|| received cisplatin for treatment across multiple tumour types,
|| AKI occurred in 31.5% of patients, with a median initial decline
||
|| in estimated GFR (eGFR) of 10 mL/min/1.73 m2 (25th and 75th
||
|| percentiles, 41.5 and 23.3 mL/min/1.73 m2). The mean
|| follow-up was 6 years. Most patients experienced small but per-
||
|| manent declines in eGFR, but none progressed to end-stage
|| renal disease requiring dialysis [25]. In patients with CKD risk
||
|| factors, particularly cardiac disease and NSAID use, avoidance
|| of administration of cisplatin to patients due to the high
||
|| incidence of AKI should be considered [26]. According to
|| Funakoshi et al. [27] it is recommended to use the new equation
||
|| (CKD-EPI) to estimate GFR instead of creatinine clearance for
|| the evaluation of renal function when cisplatin-containing che-
||
|| motherapy is used. The authors stressed that other formulae, i.e.
|| Cockcroft-Gault and 24 h creatinine clearance, overestimated
||
|| renal function in patients with impaired kidney function. To
|| prevent cisplatin-induced kidney injury, the administration of
||
|| lower doses of cisplatin in comparison with prior therapies,
|| and concomitant hydration with intravenous isotonic saline
||
||| should be introduced. Discontinuing cisplatin is generally indi-
|| cated in patients who develop evidence of progressive renal
|| impairment.
J. Małyszko et al.
Table 1. Anticancer drugs, type of nephrotoxicity, mechanism and prevention of renal adverse events

Medication Nephrotoxicity Mechanism of action Preventive measures

Alkylating agents Hyponatraemia-SIADH Direct effect on distal tubules Adequate hydration
cyclophosphamide haemorrhagic cystitis proximal tubular damage by use of Mesna or N-
ifosphamide Fanconi syndrome, renal tubular acidosis, nephrogenic acrolein and chloroacetaldehyde acetylcysteine
diabetes insipidus electrolyte monitoring
Antitumour antibiotics DITMA Direct endothelial injury Drug discontinuation,
Mitomycin C supportive care
Antimetabolites AKI non-oliguric (high dose) Precipitation of methotrexate and Adequate hydration
methotrexate Hyponatraemia-SIADH its crystals urine alkalinization,
pemetrexed AKI, acute tubular necrosis, renal tubular acidosis, dia- Decrease in GFR due to arteriolar forced diuresis
gemcitabine betes insipidus or mesangial cell constriction Drug discontinuation,
clofarabine DITMA supportive care
AKI
Thalidomide and AKI, Crystal nephropathy Adequate hydration
derivatives Interstitial nephritis
Vinca alkaloids Hyponatraemia SIADH
DITMA
Platinum derivatives Renal failure, Tubular injury Aggressive hydration

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

renal tubular acidosis, hypomagnesaemia (dose-related Forced diuresis
and cumulative)
Recurrent salt wasting
Proteasome inhibitors Thrombotic microangiopathy Drug discontinuation,
AKI supportive care
Anti-angiogenesis Proteinuria, nephrotic syndrome Anti-VEGF antibodies
drugs Hypertension
VEGF pathway inhibi- AKI, thrombotic microangiopathy
tors, TKI
EGFR pathway Hypomagnesaemia Tubular injury
inhibitors
BRAF inhibitors AKI, acute interstitial nephritis acute tubular necrosis, Tubular toxicity
Fanconi syndrome, electrolyte disturbances SIADH
ALK inhibitors AKI Supportive care
Checkpoint inhibitors Acute interstitial nephritis Suppression of T-cell immunity
Anti-PD-1 and PDL-1 Acute interstitial nephritis, AKI, acute tubular necrosis, cell-mediated immunity, poten-
therapies acute tubular injury, nephrotic syndrome tial autoimmune mechanism
Anti-CTLA-4 antibody
Interleukin-2 AKI Capillary leak syndrome leading Control volume and
to prerenal AKI haemodynamic status
Avoid other
nephrotoxins
Rituximab AKI, electrolyte disturbances Tumour lysis syndrome
Interferons Proteinuria, nephrotic syndrome Minimal changes
Thrombotic microangiopathy
AKI, acute kidney injury; SIADH, syndrome of inappropriate antidiuretic hormone secretion; DITMA, drug-induced thrombotic microangiopathy; VEGR, vascular endothelial growth
factor; VEGFR, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor-2; BRAF, v-Raf murine sarcoma
viral oncogene homologue B; ALK, anaplastic lymphoma kinase; PD-1, programmed cell death protein 1; PDL-1, programmed death-ligand 1; TKI, tyrosine kinase inhibitor; CTLA-4,
cytotoxic T lymphocyte-associated antigen 4; GFR, glomerular filtration rate.

Other platinum derivatives such as carboplatin and oxalipla- ||
tin are less nephrotoxic due to the fact that the chloride in the ||
cis position is replaced by carboxylate or cyclobutane, respec- ||
||
tively [28]. In addition, they are not transported by organic cat- ||
ion transporter OCT2. Hypomagnesaemia appears to be the ||
||
most common manifestation of carboplatin nephrotoxicity, ||
although it occurs less often than with cisplatin [29]. For ||
||
patients in whom cisplatin is contraindicated or in whom there
is an increased risk of nephrotoxicity, the substitution of carbo-
platin for cisplatin can be considered. However, due to the fact
that the relative activity of cisplatin and carboplatin differs, one
should determine whether or not this is a feasible approach.
Alkylating agents
Cyclophosphamide and ifosfamide are responsible for hae- ||
morrhagic cystitis. Acrolein is believed to be the major cause of |
this specific bladder toxicity. The major metabolite of ifosfa-
mide is chloroacetaldehyde, which is directly toxic to the tubu-
lar cells [30, 31].
Both cyclophosphamide and ifosfamide can also cause the
syndrome of inappropriate antidiuretic hormone secretion
(SIADH), similarly to melphalan [32]. Chemotherapy-induced
nausea may also play a contributory role, since nausea is a
|| potent stimulus to ADH release. Hyponatraemia typically
|| occurs acutely and resolves within 24 h after discontinuation
||
|| of the drug [32]; however, caution should be exercised in
|| patients treated with high-dose intravenous cyclophosphamide
||
|| together with high fluid load to prevent haemorrhagic cystitis
|| (Table 1).
||
||| Nephrotoxicity is more likely with ifosfamide, a synthetic
structural isomer of cyclophosphamide. Ifosfamide nephrotox-
|
icity manifests as an acute tubular dysfunction in the proximal

Chemotherapy-associated nephrotoxicity 927

tubule in the form of metabolic acidosis with a normal anion ||
gap (hyperchloraemic acidosis) due to type 1 (distal) or type 2 ||
(proximal) renal tubular acidosis, Fanconi syndrome with
||
||
hypophosphataemia induced by decreased proximal phosphate ||
reabsorption, which can lead to rickets in children, renal gluco-
||
||
suria, aminoaciduria and a marked increase in beta-2- ||
microglobulin excretion, polyuria due to nephrogenic diabetes
||
||
insipidus and hypokalaemia, which may be severe, resulting ||
||
from increased urinary potassium losses [33–35]. In addition to
tubular dysfunction, ifosfamide therapy can lead to a reduction
in GFR [34]. As risk factors for ifosphamide nephrotoxicity
include cumulative dose, young age (below 4–5 years), prior
nephrectomy and coadministration of cisplatin, prevention of
renal adverse effects should be achieved by limiting the cumula-
tive dose, in particular in patients with risk factors. Other strat-
egies, including Mesna or N-acetylcysteine have been evaluated,
with unproven efficacy.
Pemetrexed is a derivative of methotrexate, antifolate agents
that inhibit enzymes involved in purine/pyrimidine metabolism
by inhibiting RNA/DNA synthesis. It is approved for treatment
of advanced non-small cell lung cancer and pleural mesothe-
lioma. Therapy with pemetrexed could be associated with
decline in creatinine clearance, AKI and other forms of renal
damage (including acute tubular necrosis, renal tubular acidosis
and diabetes insipidus) [45, 46]. AKI with minimal proteinuria,
|| which stabilizes with drug discontinuation, could also progress
|| to permanent CKD [47, 48].
||
|| Gemcitabine, a nucleoside pyrimidine analogue, can cause
|| drug-induced thrombotic microangiopathy (DITMA) by both
||
|| immune- and toxicity-mediated mechanisms [49, 50]. This is one
|| of the more common chemotherapeutic agents responsible for
||
|| DITMA. The mechanism appears to be dose-related in most
|| patients [50]. Patients with immune-mediated DITMA may have
||
|| a history of daily exposure to the implicated drug for less than 2–

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

|| 3 weeks, while in the case of toxicity-mediated mechanism, symp-
Nitrosoureas ||
|| toms may develop gradually over weeks to months. Management
Prolonged therapy with nitrosoureas BCNU (carmustine), || of DITMA involves drug discontinuation and supportive care. In
||
CCNU (lomustine), methyl-CCNU (semustine) and streptozocin || the case of immune-mediated DITMA, the implicated agent
can cause a slowly progressive, chronic interstitial nephritis that is || must be completely avoided for life, whereas re-exposure to the
||
generally irreversible [36]. The exact mechanism of nephrotoxicity || implicated drug may be possible in selected cases of toxicity-
is not completely elucidated; it may be due to alkylation of tubular || mediated DITMA. However, the best possible solution is to avoid
||
cell proteins. In the case of streptozotocin, mild proteinuria or an || an implicated drug when other alternatives are available.
asymptomatic elevation in the plasma creatinine concentration is || Clofarabine, a purine nucleoside analogue, is approved for the
||
usually the first sign of renal involvement, followed by signs of || treatment of refractory paediatric acute lymphoblastic leukaemia,
proximal tubular damage (e.g. phosphaturia, glycosuria, aminoa-
|| as well as adult acute myelogenous leukaemia [51]. Data from
||
ciduria, uricosuria and bicarbonaturia) [37–39]. || clinical trials, the Food and Drug Administration (FDA) and case
|| reports have revealed various grades of nephrotoxicity, with AKI
||
Antitumour antibiotics || being the predominant finding ranging from 10 to 36% [52]. The
|| actual type and mechanism of nephrotoxicity is not known.
Mitomycin C may cause nephrotoxicity due to direct endo- ||
thelial injury in the kidney [40]. The most common form is ||
|| Thalidomide and derivatives
TMA. It is most likely to occur after at least 6 months of ther- ||
apy, and the overall incidence is related to cumulative dose [40]. || Lenalidomide and pomalidomide are analogues of thalido-
||
It usually presents as slowly progressive renal failure, hyperten- || mide. The former is used in the treatment of multiple myeloma
sion and a relatively bland urine sediment. || and myelodysplastic syndrome, the latter is indicated for the
||
|| treatment of multiple myeloma refractory to at least two prior
Antimetabolites || therapies. Lenalidomide was reported to cause renal failure,
||
Methotrexate, dihydrofolate reductase inhibitor and its || including a case of biopsy-proven acute interstitial nephritis
metabolite (7-OH methothrexate) are filtered by glomeruli and || [53, 54]. Recently Baird et al. [55] described a case of AKI due
||
secreted by tubules [41]. Methotrexate in high doses (over 500 || to crystal nephropathy in patient given pomalidomide and
mg/m2) can cause AKI, mainly due to AKI resulting from pre- || fluoroquinolone.
||
cipitation of methotrexate and its metabolite crystals in the distal ||
tubular lumen and direct tubular injury with necrosis (formation || Vinca alkaloids
||
of oxygen radicals associated with lowered adenosine deaminase || Vinca alkaloids such as vincristine, vinblastine and vinorel-
activity) [42]. Methotrexate can also produce a transient decrease
|| bine may contribute to SIADH [56, 57]. A causal association of
||
in GFR due to afferent arteriolar constriction or mesangial cell || vincristine with DITMA was also reported [58].
constriction that produces reduced glomerular capillary surface
||
||
area, diminished glomerular capillary perfusion and pressure ||
[43]. The prevalence of AKI induced by methotrexate was
||
|| TARGETED AGENTS
reported to be about 2% [44], but may be even higher. Typically, ||
||
AKI induced by high-dose methotrexate treatment is non- || The National Cancer Institute defines a targeted therapy as ‘a
oliguric and reversible, with a serum creatinine peak within the || type of treatment that uses drugs or other substances to identify
||
first week. The risk of AKI could be minimized but not elimi- || and attack specific types of cancer cells with less harm to normal
nated by adequate hydration to achieve high urine flow together ||| cells. Some targeted therapies block the action of certain
with urine alkalinization to a pH above 7.0 (it increases metho- || enzymes, proteins, or other molecules involved in the growth
||
trexate solubility). It can also be responsible for SIADH. and spread of cancer cells’ [59]. The most commonly used

928 J. Małyszko et al.

cancer therapies are targeted to proteasome, vascular endothe- ||
lial growth factor (VEGR) and vascular endothelial growth fac- ||
tor receptor (VEGFR), epidermal growth factor receptor
||
||
(EGFR), human epidermal growth factor receptor-2 (HER2), ||
dimerizations of HER2, v-Raf murine sarcoma viral oncogene
||
||
homologue B (BRAF), anaplastic lymphoma kinase (ALK), pro- ||
grammed cell death protein 1 (PD-1) and its ligand (PDL-1),
||
||
receptor activator of nuclear factor kappa beta ligand (RANKL) ||
||
and mammalian target of rapamycin (mTOR). ||
||
Proteasome inhibitors
||
||
||
The selective proteasome inhibitor carfilzomib received ||
accelerated approval in the USA in 2012 for single-agent use in ||
||
patients with relapsed and refractory multiple myeloma. It ||
appeared from clinical studies that the kidneys were not a major ||
||
pathway for carfilzomib clearance, because <1% of the total ||
administered dose is recoverable from urine samples 24 h after ||
||
dosing [60]. The treatment of multiple myeloma may also lead ||
to renal dysfunction, owing to the sensitivity of the organ to ||
||
injury from tumour lysis syndrome or intravenous contrast
dyes used for positron emission tomography scans and com-
puted tomography scans, which can aggravate damage caused
by light chains and/or promote aggregate formation [61].
Recently, use of carfilzomib was reported to be associated with
TMA and podocytopathy [62], tumour lysis-like phenomenon
[63], worsening of kidney function or AKI [64]. As highlighted
by Perazella and Izzedine [3], there is a very low incidence of
FDA-reported adverse renal events with carfilzomib. It may be
due to the transient nature of the injury not being reported to
the FDA. However, one should exercise caution with carfilzo-
mib therapy, even though renal toxicity is transient in most of
the cases.
VEGF pathway inhibitors
VEGF pathway inhibitors include VEGF ligand inhibitors,
which bind to and inhibit ligand binding to the VEGFR, thus
preventing activation of the receptor as bevacizumab or targeted
to VEGFR2 ramucirumab; and antiangiogenic small molecule
tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopa-
nib, ponatinib, axitinib, cabozantinib, lenvatinib, vandetanib),
FIGURE 3: Effects of anti-vascular endothelial growth factor
(VEGF) therapy.
Chemotherapy-associated nephrotoxicity
which block the intracellular domain of the VEGFR and a solu-
ble recombinant decoy that binds to circulating VEGF, afliber-
cept (VEGF-Trap) [65]. In normal kidney, VEGF is produced
by the podocytes that normally express VEGF receptor present
on glomerular and peritubular endothelium and mesangial
cells. Local synthesis of VEGF is responsible for maintenance of
normal glomerular function and integrity of the glomerular
basement membrane [66]. Thus, the most common manifesta-
tion of kidney damage is proteinuria, even nephrotic syndrome
with hypertension [67]. Effects of VEGF blockade are depicted
on Figure 3. However, the exact mechanism underlying protei-
nuria is not known. It is suggested that pre-existing renal disease
and a diagnosis of renal cell carcinoma may predispose to pro-
teinuria [68–71]. In addition, the degree of proteinuria appears
to be dose-dependent in bevacizumab-treated patients. The risk
of proteinuria is increased when bevacizumab is combined with
chemotherapy [69]. In the MARS study, de novo proteinuria
Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021
occurred in 36.4, 72, 1 and 15% while hypertension was diag-
nosed in 17.1, 22, 1 and 12.9% of bevacizumab-treated patients
with ovarian [72], lung [73] and breast cancer [74], respectively.
||
|| Among patients with renal cell cancer treated with antiangio-
|| genic TKIs, the occurrence of mild and asymptomatic proteinu-
||
|| ria was observed in 21–63%, but heavy proteinuria was reported
|| in up to 6.5% of patients [75]. As reported by Wu et al. [76],
||
|| bevacizumab treatment resulted in mild proteinuria in 21–63%,
|| but grade 3 or 4 proteinuria (defined as 3þ on dipstick, >3.5 g
||
|| of protein/24 h, or nephrotic syndrome) affected 2% of patients.
|| In a phase III trial with aflibercept with chemotherapy, protei-
||
|| nuria developed in 62% of patients relative to 41% of those
|| treated with chemotherapy alone. Proteinuria was severe (grade
||
|| 3 or 4) in 7.8 versus 1.2% [77]. Results of kidney biopsies per-
|| formed in patients with proteinuria receiving VEGF-targeted
||
|| agents included TMA, collapsing glomerulopathy, proliferative
|| glomerulonephritis and isolated reports of cryoglobulinaemic
||
|| and immune complex glomerulonephritis [77–80]. However,
|| the data are sparse. The most common causative agent was bev-
||
|| acizumab. Evidence-based guidelines for management of pro-
|| teinuria in patients receiving VEGF-targeted agents are lacking.
||
|| Although discontinuation of the anti-VEGF agent results in a
||
|| significant reduction in proteinuria, persistence is common
|| [81]. Nephroprotective therapy with an angiotensin-converting
||
|| enzyme inhibitor or angiotensin receptor blocker may lower
|| intraglomerular pressure and diminish protein excretion.
||
|| Since the TKIs have an anti-VEGF effect, similar renal
|| TMA-like findings can be seen with them as well [82]. In addi-
||
|| tion, a preeclampsia-like syndrome has been observed during
|| sunitinib therapy [83, 84]. Proteinuria was generally related to
||
|| TMA in these patients. Both the hypertension and proteinuria
|| were dose related. The development of hypertension is also
||
|| linked to a positive antitumour response [85]. Importantly, the
|| kidney injury from bevacizumab can be irreversible [82]. Both
||
|| sunitinib and sorafenib can also cause acute and chronic inter-
|| stitial nephritis, as well as a see-saw effect of chronic interstitial
||
|| and endothelial damage leading to CKD [86]. The multitargeted
|| TKIs such as imanitib and novel newer TKIs such as dasatinib
||
||| and nilotinib have been linked to kidney dysfunction and subse-
|| quently to CKD [82]. Imatinib, sunitinib and sorafenib may
|| contribute to hypophosphataemia due to inhibition of platelet-
929
derived growth factor receptors expressed on osteoclasts, || ALK inhibitors
decreased bone resorption, and calcium and phosphate egress || Crizotinib is used for treatment of non-small cell lung cancer
from the bone and a rise in parathyroid hormone levels and
||
|| with ALK fusion. A relatively common adverse event appears to
phosphaturia [82]; however, the exact mechanism is not known. || be hypophosphataemia; in addition, drug-induced reductions
Impaired renal function and diabetes insipidus have been
||
|| in GFR were also reported in a crizotinib-treated patient, pre-
reported in patients with medullary thyroid cancer and lung || dominantly during the first 2 weeks of therapy [101]. Camidge
cancer receiving vandetanib although causality has not been
||
|| et al. [102] suggested that the acute effects on creatinine clear-
proven [87, 88]. || ance reflect an effect of the drug on creatinine excretion rather
||
|| than a true reduction in GFR. However, recently a case of acute
EGFR pathway inhibitors
||
|| renal failure accompanied by proteinuria and haematuria was
Monoclonal antibodies targeting the EGFR (cetuximab, pan-
|| reported [103].
||
itumumab, necitumumab, matuzumab) are associated with the ||
progressive development of hypomagnesaemia due to renal
||
|| Anti-HER2 therapies
magnesium wasting [89–91]. Magnesium reabsorption in the ||
|| Available anti-HER2 cancer therapies include two monoclo-
distal convoluted tubule is partly dependent on EGFR activity || nal antibodies, trastuzumab and pertuzumab, and the TKI lapa-
on the basolateral membrane. This leads to integration of the ||
|| tinib. Trastuzumab is a recombinant humanized monoclonal

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

cation channel transient receptor potential M6 into the apical || antibody directed against the extracellular domain of the HER2,
membrane. It enables the reabsorption of magnesium from the ||
|| whereas pertuzumab is directed to a different epitope of the
urinary space [92]. Cetuximab prevents EGF binding to its || extracellular domain of the HER2 as compared with trastuzu-
receptor causing magnesium wasting [92]. Hypomagnesaemia ||
|| mab. Pertuzumab blocks the dimerization of HER2, which is
resolves after treatment is discontinued. || essential for cell activation and proliferation. Both drugs have
||
|| no reported renal toxicity. However, when trastuzumab is given
BRAF inhibitors || in combination with anthracyclines, known for cardiotoxicity
||
BRAF is a human gene that makes B-raf protein (fibrosar- || [104], cardiorenal syndrome was observed [105]. Breast cancer
|| type containing HER2 overexpression is associated with predis-
coma kinase B), which is involved in transmitting signals within ||
cells involved in cell growth. The discovery of mutations in || position to cardiotoxicity [106]. What is even more important,
|| as reported by Russo et al. [107], is that the cardiotoxicity of
BRAF [93], part of the MAPK signalling pathway, in 2002 [91] ||
changed targeted therapy in malignant melanoma, at least as it || trastuzumab might be increased in patients with CKD. As sug-
|| gested by Albini et al. [108] cardiorenal syndrome may occur,
stands currently [94–96]. Vemurafenib and dabrafenib are ||
potent inhibitors of the kinase domain in mutant BRAF, and || and/or be worsened by the presence of pre-existing CKD.
|| However, data from the HERCULES trial suggest that the car-
are approved for the treatment of patients with advanced mela- ||
noma whose tumours contain a BRAF V600 mutation. In the || diac tolerance of trastuzumab in combination with epirubicin
|| and cyclophosphamide is acceptable [109]. It was also reported
most recent review, Wanchoo et al. [97] presented the data on ||
nephrotoxicities of these agents. They stressed that, despite the || in this trial that the best prognostic cut-off value for eGFR and
|| cardiotoxicity was 78 mL/min/1.73 m2 [109].
fact that the initial trials did not signal any renal toxicities with ||
the BRAF inhibitors, recent case reports, case series and FDA ||
||
adverse reporting systems have uncovered significant nephro- || Checkpoint inhibitors. PD-1, PDL-1 and cytotoxic T
toxicity of BRAF inhibitors, which is most pronounced with ||
|| lymphocyte-associated antigen 4 (CTLA-4) are monoclonal
vemurafenib [97]. Decline in creatinine clearance generally || antibodies that target inhibitory receptors expressed on T cells,
occurs within the first 2 months of therapy with vemurafenib ||
|| other immune cells and tumour cells. Checkpoint inhibitors
[98]. Recovery after treatment has been variable. Renal toxicity || (CPIs) enhance tumour-directed immune responses by inhibit-
seen with vemurafenib shows a male predominance. AKI is also ||
|| ing CTLA-4 and PD-1/PDL-1.
reported with dabrafenib, although it is less common than with ||
vemurafenib [99]. BRAF inhibitor-related toxicity includes: ||
|| Anti-PD-1 and -PDL-1 therapies
allergic interstitial disease, acute tubular necrosis, proximal tub- ||
ular damage (Fanconi syndrome), non-nephrotic-range protei-
|| There are several monoclonal antibodies directed against
||
nuria, acute/subacute decrease in GFR by 20–40%, electrolyte || PD-1, such as nivolumab, pembrolizumab and lambrolizumab,
disturbances such as hypophosphataemia, hyponatraemia and
|| and MPDL-3280A, directed against PDL-1. In patients treated
||
hypokalaemia. Urine sediment may be either active with hae- || with nivolumab, hypophosphataemia was found in 3% [110],
maturia, proteinuria and white blood cells, or may show granu-
|| and proteinuria and hypertension were reported in 16.7% [111],
||
lar casts or white blood cell casts [97]. In the experimental || whereas in lambrolizumab-treated patients, renal failure
||
animal model, BRAF was shown to be expressed and localized || occurred in 2% [112]. Renal dysfunction was also reported for
in developing and mature glomerular podocytes [100], whereas || pembrolizumab [113]. Recently, Shirali et al. [114] described six
||
in a clinical setting the presumed mechanism of nephrotoxicity || cases of acute interstitial nephritis in patients with lung cancer
is tubular toxicity. It is recommended to routinely monitor ||| treated with anti-PD-1 antibodies. They suggested that the asso-
serum creatinine and electrolytes, and estimate GFR prior to the || ciation of acute interstitial nephritis with these drugs raised the
||
first administration of dabrafenib and vemurafenib. possibility that PD-1 inhibitor therapy may release suppression

930 J. Małyszko et al.

of T-cell immunity that normally permits renal tolerance of | [128], mainly due to hypovolaemia. On the other hand, there
drugs known to be associated with acute interstitial nephritis.
|| may also be some direct renal injury. Recombinant interferon
||
|| alpha (IFN-a) can cause proteinuria, even in the nephrotic
An anti-CTLA-4 antibody || range, which is associated with minimal change disease on kid-
||
Ipilimumab is approved for use in patients with advanced || ney biopsy [129]. Rarely, TMA is seen, mainly in patients with
|
melanoma. Kidney injury was described as a rare but severe || chronic myeloid leukaemia treated with high doses of IFN-a
|
complication of ipilimumab therapy. Nephrotic syndrome, || over long periods of time [130].
|
acute tubular injury/acute tubular necrosis, acute interstitial ||
|
nephritis and AKI have been reported. Kidney biopsies revealed ||
|
acute granulomatous interstitial nephritis [115] and lupus || A N T I R E S O R P T I V E A G E N T S
|
membranous nephropathy [116]. Steroid therapy has been |||
associated with improvement in renal function in some reports ||| Bone metastases are a common site of cancer recurrence for
[117, 118], although the mechanism of kidney injury is not well ||| many types of solid tumours. They cause substantial morbidity,
understood. Cell-mediated immunity [119] and potential auto- ||| including fractures, spinal cord compression, the need for sur-
immune mechanism [116] may be implicated based on the ben- ||| gery or radiation therapy to bone for a symptomatic metastasis,
eficial effects of steroids. However, in a recent study on 13 ||| and hypercalcaemia of malignancy. Osteoclast inhibitors
patients with CPI-induced AKI who underwent kidney biopsy, ||| (bisphosphonates and denosumab), which are not anticancer

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

Cortazar et al. [120] reported that the prevalent pathologic ||| drugs, significantly reduce the frequency of skeletal-related
lesion was acute tubulointerstitial nephritis (12 out of 13), ||| events in patients with bone metastases from a wide variety of
though with a longer latency period. Patients were treated with ||| cancer types [131, 132]. However, therapy with osteoclast inhib-
different CPIs or their combinations, i.e. ipilimumab alone (n ¼ ||| itors has been associated with the risk of developing electrolyte
6), ipilimumab in combination with nivolumab (n ¼ 4), nivolu- ||| disturbance (most notably hypocalcaemia due to denosumab),
mab alone (n ¼ 1) and pembrolizumab alone (n ¼ 2). ||| acute phase reactions and renal toxicity (intravenous
Histological features were similar to other causes of drug- ||| bisphosphonates).
induced acute tubulointerstitial nephritis. The authors |||
suggested that CPI-induced AKI may be caused by a unique ||| RANKL-targeted therapies
mechanism of action linked to reprogramming of the immune ||
| Denosumab is a monoclonal antibody inhibiting the osteo-
system, resulting in loss of tolerance.
|| protegerin/RANK/RANKL by blocking RANKL. It is used in
||
|| clinical practice to prevent skeletal-related events in patients
mTOR inhibitors || with bone metastases and malignancy-associated hypercalcae-
||
Everolimus and sirolimus, used in solid organ transplanta- || mia [133]. Denosumab is better tolerated than zoledronic acid
|
tion in the prevention of graft rejection, inhibit mTOR. They || with fewer renal side effects [134, 135]; however, hypocalcaemia
|
are also named proliferation signal inhibitors (PSI). Everolimus || is more common [136].
|
and temsirolimus are used in clinical oncology to treat ||
|
advanced renal cell carcinoma. Their use may be associated ||| Bisphosphonates
with proteinuria, hypertension and hypophosphataemia [121– || | Bisphosphonates all have in common the P–C–P structure,
123]. Temsirolimus-associated glomerulopathy has also been ||| which is similar to the P–O–P structure of native pyrophos-
described [124]. || phate. They are used to prevent bone resorption. Alendronate,
||
|| neridronate, ibandronate, pamidronate, risedronate and zole-
Inhibitor of Bruton’s tyrosine kinase || dronic acid have a nitrogen group and are called nitrogen-
|
Ibrutinib, an orally active inhibitor of Bruton’s tyrosine kin- ||| containing bisphosphonates in contrast to etidronate and
ase, a mediator of the B-cell receptor signalling pathway that ||| tiludronate, which do not. There are important differences
inhibits malignant B-cell survival, was approved as a single ||| among the bisphosphonates in mechanism of action, potency
agent for the treatment of mantle cell lymphoma, and this drug ||| and toxicity. The nitrogen-containing bisphosphonates are
can be associated with AKI, sometimes even having a fatal out- ||| more potent inhibitors of bone resorption than the simple
come [125].
|| bisphosphonates. They act primarily by inhibiting the enzyme
||
|| farnesyl pyrophosphate (FPP) synthase in the mevalonate path-
|| way (cholesterol biosynthetic pathway) and their relative antire-
||
OTHER BIOLOGIC AGENTS || sorptive efficacy is related to the potency within which they
|| inhibit FPP synthase [137, 138]. Simple bisphosphonates are
||
Rituximab is a monoclonal antibody directed against CD20 that || metabolized by osteoclasts to metabolites that exchange with
|
is active in the treatment of lymphoid malignancies. Rituximab || the terminal pyrophosphate moiety of adenosine triphosphate
|
has been associated with electrolyte disturbances and AKI in || (ATP), resulting in an ATP that cannot be used as a source of
|
patients with high circulating tumour cells (>25 000/lL) or a || energy [137, 138]. The osteoclasts then undergo apoptosis.
||
high tumour burden [126, 127]. || Pamidronate and zoledronic acid are approved for prevention
Recombinant human IL-2 can induce a relatively severe || of skeletal events in patients with advanced malignancy.
|
capillary leak syndrome, leading to oedema, plasma volume || Nephrotic syndrome has been described with the use of
|
depletion and a reversible fall in GFR, which may result in AKI | pamidronate, as well as AKI. A number of mechanisms have

Chemotherapy-associated nephrotoxicity 931


FIGURE 4: Chemotherapy-induced kidney injury.
been proposed, including collapsing FSGS, FSGS-non-specified ||
and minimal change disease [139–143]. Intravenous zolendro- ||
nate has been associated with AKI, mainly when higher than
||
||
recommended doses (8 mg instead of 4 mg) were administered ||
and when infusion time was shorter than 15 min [144–146].
||
||
AKI induced by zoledronic acid may be different from ||
||
pamidronate-induced AKI. Markowitz et al. [146] showed toxic ||
acute tubular necrosis without evidence of glomerular damage, ||
||
i.e. proteinuria in zolendronate-induced AKI. ||
Bisphosphonates are excreted mainly by the kidneys, and ||
||
they diffuse passively into tubular cells dependent only on ||
serum concentration and protein binding. Consequently, they ||
||
accumulate in tubular cells and can induce apoptosis leading to ||
the development of AKI [146, 147] due to tubular necrosis. ||
||
Typically, this presents as a gradual rise in serum creatinine ||
over months that is only slowly reversed after drug discontinua-
tion. However, with long-term treatment, patients may develop
albuminuria that improves upon discontinuation of the drug.
On the other hand, collapsing FSGS was also reported with the
use of intravenous zolendronate [148].
The mechanism of kidney injury is unknown. Intravenous
bisphosphonates may directly or indirectly affect podocytes. By
acting on osteoclasts with cytoskeleton resembling podocytes,
bisphosphonates, by inhibiting the mevalonate pathway, alter
cell signalling, lead to cytoskeletal abnormalities and induce
apoptosis. In addition, bisphosphonates disrupt farnesyl pyro-
phosphate synthase causing accumulation of a precursor, iso-
pentenyl pyrophosphate (IPP), which can bind to a receptor
and cause the release of TNF-a. Synthesis of TNF-a is hypothe-
sized to cause an acute-phase reaction, a widely known side
effect of intravenous bisphosphonates [149]. TNF-a is also a
932
Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021
potent proinflammatory cytokine and important mediator of
inflammatory kidney damage. Inhibition of TNF-a production
or action markedly reduced the nephrotoxicity of cisplatin [15].
Thus the mechanism of injury involving TNF alpha might also
be relevant for bisphosphonates. AKI in patients receiving intra-
venous bisphosphonates may be minimized by observing rec-
ommended infusion times, optimizing hydration prior to
bisphosphonate administration (particularly for patients with
marked Bence-Jones proteinuria), avoiding concurrent nephro-
toxic medications and strict adherence to package insert
information.
SUMMARY
|| A number of antineoplastic agents are cleared by the kidney, and
||
|| may affect their function, including chemotherapeutic drugs,
|| molecular targeted therapies, analgesics, antibiotics, radiophar-
||
|| maceuticals, and radiation and bone-targeted therapies. These
|| drugs can cause a variety of renal disease and electrolyte disor-
||
|| ders. Chemotherapy-induced kidney injuries are shown in
|| Figure 4. The incidence, severity and pattern of nephrotoxicity
||
|| depends on the drug. Moreover, it has been recognized that novel
|| treatment with targeted drugs offers superior patient survival
||
|| rates compared with standard chemotherapy. However, these
|| drugs have a range of nephrotoxic adverse effects. As reported by
||
|| Jhaveri et al. [150], on the basis of the Food and Drug
|| Administration Adverse Event Reporting System for nephrotox-
||
|| icity of selected novel targeted therapies reported, renal impair-
|| ment was found in 42.2%, with ipilimumab, vemurafenib and
||
| ceruximab being the most common offending drug. Electrolyte
J. Małyszko et al.
disorders were reported in 47.3% of adverse events, with hypoka- 18. Xu EY, Perlina A, Vu H et al. Integrated pathway analysis of rat urine
|| metabolic profiles and kidney transcriptomic profiles to elucidate the sys-
laemia being the most prevalent, and hypertension in 10.5%. ||
Thus, early diagnosis and prompt therapy of these kidney and
|| tems toxicology of model nephrotoxicants. Chem Res Toxicol 2008; 21:
|| 1548–1561
electrolyte disorders are essential in clinical practice. Monitoring || 19. Townsend DM, Deng M, Zhang L et al. Metabolism of Cisplatin to a neph-
of kidney function is crucial both before and during treatment to
||
|| rotoxin in proximal tubule cells. J Am Soc Nephrol 2003; 14: 1–10
identify nephrotoxicity. It is also necessary to adjust dosage || 20. Baliga R, Ueda N, Walker PD et al. Oxidant mechanisms in toxic acute
accordingly. As in every specialty, excluding nephrology, patients
|| renal failure. Drug Metab Rev 1999; 31: 971–977
|| 21. Ciarimboli G, Ludwig T, Lang D et al. Cisplatin nephrotoxicity is critically
with pre-existing CKD are excluded from clinical trials; thus, ||
|| mediated via the human organic cation transporter 2. Am J Pathol 2005;
nephrotoxicity is not commonly reported in randomized con- || 167: 1477–1484
trolled trials, whereas it may occur in routine practice. Thus, the || 22. Torres R, Velazquez H, Chang JJ et al. Three-dimensional morphology by
|| multiphoton microscopy with clearing in a model of cisplatin-induced
issue of chemotherapy-associated nephrotoxicity needs to be ||
addressed in order to provide data on how to deal with these || CKD. J Am Soc Nephrol 2016; 27: 1102–1112
|| 23. Lajer H, Kristensen M, Hansen HH et al. Magnesium depletion enhances
complications in order to optimize the care of cancer patients. || cisplatin-induced nephrotoxicity. Cancer Chemother Pharmacol 2005; 56:
|| 535–542
||
|| 24. Jackson AM, Rose BD, Graff LG et al. Thrombotic microangiopathy and
CONFLICT OF INTEREST STATEMENT || renal failure associated with antineoplastic chemotherapy. Ann Intern Med
|| 1984; 101: 41–44
|
The results presented in this paper have not been published pre- |||

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

25. Latcha S, Jaimes EA, Patil S et al. Long-term renal outcomes after cisplatin
viously in whole or part. || treatment. Clin J Am Soc Nephrol 2016; 11: 1173–1179
|| 26. Sato K, Watanabe S, Ohtsubo A et al. Nephrotoxicity of cisplatin combina-
|| tion chemotherapy in thoracic malignancy patients with CKD risk factors.
||
REFERENCES || BMC Cancer 2016; 16: 222
|| 27. Funakoshi Y, Fujiwara Y, Kiyota N et al. Validity of new methods to evalu-
1. Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with cancer ||
| ate renal function in cancer patients treated with cisplatin. Cancer
and its treatment: an update. J Am Soc Nephrol 2005; 16: 151–161 || Chemother Pharmacol 2016; 77: 281–288
2. Jhaveri KD, Shah HH, Calderon K et al. Glomerular diseases seen with can- ||
| 28. McDonald BR, Kirmani S, Vasquez M et al. Acute renal failure associated
cer and chemotherapy: a narrative review. Kidney Int 2013; 84: 34–44 || with the use of intraperitoneal carboplatin: a report of two cases and review
3. Perazella MA, Izzedine H. New drug toxicities in the onco-nephrology ||
| of the literature. Am J Med 1991; 90: 386–391
world. Kidney Int 2015; 87: 909–917 || 29. Ettinger LJ, Gaynon PS, Krailo MD et al. A phase II study of carboplatin in
4. Jhaveri KD, Shah HH, Patel C et al. Glomerular diseases associated with ||
| children with recurrent or progressive solid tumors. A report from the
cancer, chemotherapy, and hematopoietic stem cell transplantation. Adv || Childrens Cancer Group. Cancer 1994; 73: 1297–1301
Chronic Kidney Dis 2014; 21: 48–55
|| 30. Dubourg L, Michoudet C, Cochat P et al. Human kidney tubules detoxify
|
5. Jhaveri KD, Fishbane S. Nephrology Crossword: Onco-nephrology—che- || chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J
motherapy agents and nephrotoxicity. Kidney Int 2013; 84: 421–422
|| Am Soc Nephrol 2001; 12: 1615–1623
|
6. Perazella MA. Onco-nephrology: renal toxicities of chemotherapeutic || 31. Zhang J, Tian Q, Zhou S-F. Clinical pharmacology of cyclophosphamide
|| and ifosfamide. Curr Drug Ther 2006; 1: 55–84
agents. Clin J Am Soc Nephrol 2012; 7: 1713–1721 |
7. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med || 32. Bressler RB, Huston DP. Water intoxication following moderate-dose
|| intravenous cyclophosphamide. Arch Intern Med 1985; 145: 548–549
2011; 364: 1844–1854 ||
8. Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high- || 33. Skinner R, Sharkey IM, Pearson AD et al. Ifosfamide, mesna, and nephro-
grade non-Hodgkin’s lymphoma. Am J Med 1993; 94: 133–139 || toxicity in children. J Clin Oncol 1993; 11: 173–190
9. Cairo MS, Coiffier B, Reiter A et al. Recommendations for the evaluation ||
| 34. Oberlin O, Fawaz O, Rey A et al. Long-term evaluation of Ifosfamide-
of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and chil- || related nephrotoxicity in children. J Clin Oncol 2009; 27: 5350–5355
dren with malignant diseases: an expert TLS panel consensus. Br J ||
| 35. Farry JK, Flombaum CD, Latcha S. Long term renal toxicity of ifosfamide
Haematol 2010; 149: 578–586 || in adult patients-5 year data. Eur J Cancer 2012; 48: 1326–1331
10. Filipski KK, Loos WJ, Verweij J et al. Interaction of Cisplatin with the ||
| 36. Narins RG, Carley M, Bloom EJ et al. The nephrotoxicity of chemothera-
human organic cation transporter 2. Clin Cancer Res 2008; 14: 3875–3880 || peutic agents. Semin Nephrol 1990; 10: 556–564
11. Safirstein R, Miller P, Guttenplan JB. Uptake and metabolism of cisplatin ||
| 37. Broder LE, Carter SK. Pancreatic islet cell carcinoma. II. Results of therapy
by rat kidney. Kidney Int 1984; 25: 753–758 || with streptozotocin in 52 patients. Ann Intern Med 1973; 79: 108–118
12. Dobyan DC, Levi J, Jacobs C et al. Mechanism of cis-platinum nephrotox- ||
| 38. Perry DJ, Weiss RB. Nephrotoxicity of streptozocin. Ann Intern Med 1982;
icity: II. Morphologic observations. J Pharmacol Exp Ther 1980; 213: || 96: 122
551–556
|| 39. Kintzel PE. Anticancer drug-induced kidney disorders. Drug Saf 2001; 24:
|
13. Portilla D, Kaushal GP, Basnakian AG. Recent progress in the pathophysi- || 19–38
ology of acute renal failure. In: MS Runge, C Patterson (eds). Principles of ||
| 40. Groff JA, Kozak M, Boehmer JP et al. Endotheliopathy: a continuum of
Molecular Medicine, 2nd edn. Totowa, NJ: Humana Press, 2006, p. 643 || hemolytic uremic syndrome due to mitomycin therapy. Am J Kidney Dis
14. Luke DR, Vadiei K, Lopez-Berestein G. Role of vascular congestion in ||
| 1997; 29: 280–284
cisplatin-induced acute renal failure in the rat. Nephrol Dial Transplant ||| 41. Monjanel S, Rigault JP, Cano JP et al. High-dose methotrexate: preliminary
1992; 7: 1–7 || evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol
15. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine ||
| 1979; 3: 189–196
expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002; || 42. Widemann BC, Adamson PC. Understanding and managing methotrexate
110: 835–842
|| nephrotoxicity. Oncologist 2006; 11: 694–703
|
16. Ramesh G, Reeves WB. p38 MAP kinase inhibition ameliorates cisplatin || 43. Howell SB, Carmody J. Changes in glomerular filtration rate associated
nephrotoxicity in mice. Am J Physiol Renal Physiol 2005; 289: F166–F174
|| with high-dose methotrexate therapy in adults. Cancer Treat Rep 1977; 61:
|
17. Urakami Y, Okuda M, Masuda S et al. Functional characteristics and mem- || 1389–1391
brane localization of rat multispecific organic cation transporters, OCT1 ||
| 44. Widemann BC, Balis FM, Kempf-Bielack B et al. High-dose methotrexate-
and OCT2, mediating tubular secretion of cationic drugs. J Pharmacol Exp || induced nephrotoxicity in patients with osteosarcoma. Cancer 2004; 100:
Ther 1998; 287: 800–805
|| 2222–2232
|

Chemotherapy-associated nephrotoxicity 933

45. Stavroulopoulos A, Nakopoulou L, Xydakis AM et al. Interstitial nephritis 70. Zhu X, Stergiopoulos K, Wu S. Risk of hypertension and renal dysfunction
and nephrogenic diabetes insipidus in a patient treated with pemetrexed.
|| with an angiogenesis inhibitor sunitinib: systematic review and meta-anal-
||
Ren Fail 2010; 32: 1000–1004 || ysis. Acta Oncol 2009; 48: 9–17
46. Vootukuru V, Liew YP, Nally JV, Jr. Pemetrexed-induced acute renal fail- || 71. Shord SS, Bressler LR, Tierney LA et al. Understanding and managing the
ure, nephrogenic diabetes insipidus, and renal tubular acidosis in a patient || possible adverse effects associated with bevacizumab. Am J Health Syst
||
with non-small cell lung cancer. Med Oncol 2006; 23: 419–422 || Pharm 2009; 66: 999–1013
47. Rombola G, Vaira F, Trezzi M et al. Pemetrexed induced acute kidney || 72. Launay-Vacher V, Janus N, Selle F et al. Results of the MARS study on the
injury in patients with non-small cell lung cancer reversible and chronic || management of antiangiogenics’ renovascular safety in ovarian cancer.
renal damage. J Nephrol 2015; 28: 187–191
|| American Society of Clinical Oncology Annual Meeting. J Clin Oncol 2013;
||
48. Glezerman IG, Pietanza MC, Miller V et al. Kidney tubular toxicity of || 31 (Suppl): abstr 5567
maintenance pemetrexed therapy. Am J Kidney Dis 2011; 58: 817–820 || 73. Goldwasser F, Janus N, Morere JF et al. Results of the MARS study on the
49. Saif MW, Xyla V, Makrilia N et al. Thrombotic microangiopathy associ- || management of antiangiogenics’ renovascular safety in lung cancer. European
ated with gemcitabine: rare but real. Expert Opin Drug Saf 2009; 8:
|| Cancer Congress, Eur J Cancer 2013; 49 (Suppl 2): S819 (abstr 3471)
||
257–260 || 74. Gligorov J, Janus N, Daniel C et al. Results of the MARS study on the man-
50. Leal F, Macedo LT, Carvalheira JB. Gemcitabine-related thrombotic micro- || agement of antiangiogenics’ renovascular safety in breast cancer. Cancer
angiopathy: a single-centre retrospective series. J Chemother 2014; 26: || Res 2013; 73 (24 Suppl): P3–15
169–172
|| 75. Izzedine H, Massard C, Spano JP et al. VEGF signalling inhibition-induced
||
51. Faderl S, Ravandi F, Huang X et al. A randomized study of clofarabine ver- || proteinuria: mechanisms, significance and management. Eur J Cancer
sus clofarabine plus low-dose cytarabine as front-line therapy for patients || 2010; 46: 439–448
aged 60 years and older with acute myeloid leukemia and high-risk myelo- || 76. Wu S, Kim C, Baer L et al. Bevacizumab increases risk for severe proteinu-
||

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

dysplastic syndrome. Blood 2008; 112: 1638–1645 || ria in cancer patients. J Am Soc Nephrol 2010; 21: 1381–1389
52. Jhaveri KD, Chidella S, Allen SL et al. Clofarabine-induced kidney toxicity. || 77. Van Cutsem E, Tabernero J, Lakomy R et al. Addition of aflibercept to fluo-
J Oncol Pharm Pract 2014; 20: 305–308 || rouracil, leucovorin, and irinotecan improves survival in a phase III random-
53. Lipson EJ, Huff CA, Holanda DG et al. Lenalidomide-induced acute inter- || ized trial in patients with metastatic colorectal cancer previously treated with
||
stitial nephritis. Oncologist 2010; 15: 961–964 || an oxaliplatin-based regimen. J Clin Oncol 2012; 30: 3499–3506
54. Batts ED, Sanchorawala V, Hegerfeldt Y et al. Azotemia associated with || 78. George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case
use of lenalidomide in plasma cell dyscrasias. Leuk Lymphoma 2008; 49: || report and literature review. Am J Kidney Dis 2007; 49: e23–e29
1108–1115
|| 79. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II
||
55. Baird P, Leung S, Hoang H et al. A case of acute kidney injury from crystal || trial comparing bevacizumab plus carboplatin and paclitaxel with carbo-
nephropathy secondary to pomalidomide and levofloxacin use. J Oncol || platin and paclitaxel alone in previously untreated locally advanced or
Pharm Pract 2016; 22: 357–360 || metastatic non-small-cell lung cancer. J Clin Oncol 2004; 22: 2184–2191
56. Cutting HO. Inappropriate secretion of antidiuretic hormone secondary to
|| 80. Eremina V, Jefferson JA, Kowalewska J et al. VEGF inhibition and renal
||
vincristine therapy. Am J Med 1971; 51: 269–271 || thrombotic microangiopathy. N Engl J Med 2008; 358: 1129–1136
57. Garrett CA, Simpson TA, Jr. Syndrome of inappropriate antidiuretic hor- || 81. Patel TV, Morgan JA, Demetri GD et al. A preeclampsia-like syndrome
mone associated with vinorelbine therapy. Ann Pharmacother 1998; 32: || characterized by reversible hypertension and proteinuria induced by the
1306–1309
|| multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst
||
58. Kanchi H, Webb NJ, Eden OB. Hemolytic uremic syndrome secondary to || 2008; 100: 282–284
the treatment of acute lymphoblastic leukemia. J Pediatr Hematol Oncol || 82. Humphreys B, Lichtman S, Rey J et al. Renal effects of molecular targeted
2000; 22: 483–484 || therapies in oncology: a review by the Cancer and the Kidney International
59. http://www.cancer.gov/publications/dictionaries/cancer-terms?
|| Network (C-KIN). Ann Oncol 2015; 26: 1677–1684
||
cdrid=270742 (1 May 2016, date last accessed). || 83. Kappers MH, Smedts FM, Horn T et al. The vascular endothelial growth
60. Badros AZ, Vij R, Martin T et al. Carfilzomib in multiple myeloma patients || factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome
with renal impairment: pharmacokinetics and safety. Leukemia 2013; 27: || with activation of the endothelin system. Hypertension 2011; 58: 295–302
||
1707–1714 || 84. Vigneau C, Lorcy N, Dolley-Hitze T et al. All anti-vascular endothelial
61. Dimopoulos MA, Kastritis E, Rosinol L et al. Pathogenesis and treatment || growth factor drugs can induce ‘pre-eclampsia-like syndrome’: a RARe
of renal failure in multiple myeloma. Leukemia 2008; 22: 1485–1493 || study. Nephrol Dial Transplant 2014; 29: 325–332
62. Hobeika L, Self SE, Velez JC. Renal thrombotic microangiopathy and
|| 85. Azizi M, Chedid A, Oudard S. Home blood-pressure monitoring in
||
podocytopathy associated with the use of carfilzomib in a patient with mul- || patients receiving sunitinib. N Engl J Med 2008; 358: 95–97
tiple myeloma. BMC Nephrol 2014; 15: 156 || 86. Usui J, Glezerman IG, Salvatore SP et al. Clinicopathological spectrum of
63. Shely RN, Ratliff PD. Carfilzomib-associated tumor lysis syndrome. || kidney diseases in cancer patients treated with vascular endothelial growth
Pharmacotherapy 2014; 34: e34–e37
|| factor inhibitors: a report of 5 cases and review of literature. Hum Pathol
||
64. Shah JJ. Incidence and management of renal adverse events in patients || 2014; 45: 1918–1927
with relapsed and/or refractory multiple myeloma treated with single- || 87. Robinson BG, Paz-Ares L, Krebs A et al. Vandetanib (100 mg) in patients
agent carfilzomib. Oncology (Williston Park) 2013; 27 (Suppl 3): 19–23 || with locally advanced or metastatic hereditary medullary thyroid cancer. J
65. Launay-Vacher V, Aapro M, De Castro G, Jr et al. Renal effects of molecu-
|| Clin Endocrinol Metab 2010; 95: 2664–2671
||
lar targeted therapies in oncology: a review by the Cancer and the Kidney || 88. Wells SA, Jr, Gosnell JE, Gagel RF et al. Vandetanib for the treatment of
International Network (C-KIN). Ann Oncol 2015; 26: 1677–1684 || patients with locally advanced or metastatic hereditary medullary thyroid
66. Eremina V, Jefferson JA, Kowalewska J et al. VEGF inhibition and renal || cancer. J Clin Oncol 2010; 28: 767–772
||
thrombotic microangiopathy. N Engl J Med 2008; 58: 1129–1136 || 89. Tejpar S, Piessevaux H, Claes K et al. Magnesium wasting associated with
67. Launay-Vacher V, Deray G. Hypertension and proteinuria: a class-effect of || epidermal-growth-factor receptor-targeting antibodies in colorectal cancer:
antiangiogenic therapies. Anticancer Drugs 2009; 20: 81–82 || a prospective study. Lancet Oncol 2007; 8: 387–394
68. Tomita Y, Uemura H, Fujimoto H et al. Key predictive factors of axitinib
|| 90. Thatcher N, Hirsch FR, Luft AV et al.; SQUIRE Investigators.
||
(AG-013736)-induced proteinuria and efficacy: a phase II study in || Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cis-
Japanese patients with cytokine-refractory metastatic renal cell carcinoma. || platin alone as first-line therapy in patients with stage IV squamous non-
Eur J Cancer 2011; 47: 2592–2602 || small-cell lung cancer (SQUIRE): an open-label, randomised, controlled
69. Zhu X, Wu S, Dahut WL et al. Risks of proteinuria and hypertension with
|| phase 3 trial. Lancet Oncol 2015; 16: 763–774
||
bevacizumab, an antibody against vascular endothelial growth factor: sys-
tematic review and meta-analysis. Am J Kidney Dis 2007; 49: 186–193
||| 91. Kelly RJ, Billemont B, Rixe O. Renal toxicity of targeted therapies. Target
Oncol 2009; 4: 121–133
||
||

934 J. Małyszko et al.

92. Groenestege WM, Thébault S, van der Wijst J et al. Impaired basolateral 117. Forde PM, Rock K, Wilson G et al. Ipilimumab-induced immune-related
sorting of pro-EGF causes isolated recessive renal hypomagnesemia. J Clin
|| renal failure—a case report. Anticancer Res 2012; 32: 4607–4608
||
Invest 2007; 117: 2260–2267 || 118. Voskens CJ, Goldinger SM, Loquai C et al. The price of tumor control: an
93. Davies H, Bignell GR, Cox C et al. Mutations in BRAF gene in human can- || analysis of rare side effects of anti-CTLA-4 therapy in metastatic mela-
cer. Nature 2002; 417: 949–954 || noma from the ipilimumab network. PLoS One 2013; 8: e537–e545
||
94. Andrulis M, Lehners N, Capper D et al. Targeting the BRAF V600E muta- || 119. Chmiel KD, Suan D, Liddle C et al. Resolution of severe ipilimumab-
tion in multiple myeloma. Cancer Discov 2013; 3: 862–869 || induced hepatitis after antithymocyte globulin therapy. J Clin Oncol 2011;
95. Falchook GS, Long GV, Kurzrock R et al. Dabrafenib in patients with mel- || 29: e237–e240
anoma, untreated brain metastases, and other solid tumours: a phase 1
|| 120. Cortazar FB, Marrone KA, Troxell ML et al. Clinicopathological features of
||
dose-escalation trial. Lancet 2012; 379: 1893–1901 || acute kidney injury associated with immune checkpoint inhibitors. Kidney
96. Hall R, Kudchadkar R. BRAF mutations: signaling, epidemiology and clini- || Int 2016; 90: 638–647
cal experience in multiple malignancies. Cancer Control 2014; 21: 221–230 || 121. Hainsworth JD, Waterhouse DM, Penley WC et al. Sorafenib and everoli-
97. Wanchoo R, Jhaveri KD, Deray G et al. Renal effects of BRAF inhibitors: a
|| mus in advanced clear cell renal carcinoma: a phase I/II trial of the SCRI
||
systematic review by the Cancer and the Kidney International Network. || oncology research consortium. Cancer Invest 2013; 31: 323–329
Clin Kidney J 2016; 9: 245–251 || 122. Raymond E, Alexandre J, Faivre S et al. Safety and pharmacokinetics of
98. Launay-Vacher V, Zimner-Rapuch S, Poulalhon N et al. Acute renal failure || escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR
associated with the new BRAF inhibitor vemurafenib: a case series of 8
|| inhibitor, in patients with cancer. J Clin Oncol 2004; 22: 2336–2347
||
patients. Cancer 2014; 120: 2158–2163 || 123. Nouhaud FX, Pfister C, Defortescu G et al. Baseline chronic kidney disease
99. Jhaveri KD, Sakhiya V, Fishbane S. Nephrotoxicity of the BRAF inhibitors || is associated with toxicity and survival in patients treated with targeted
vemurafenib and dabrafenib. JAMA Oncol 2015; 1: 1133–1134 || therapies for metastatic renal cell carcinoma. Anticancer Drugs 2015; 26:
||

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

100. Chaib H, Hoskins BE, Ashraf S et al. Identification of BRAF as a new inter- || 866–871
actor of PLCepsilon1, the protein mutated in nephrotic syndrome type 3. || 124. Izzedine H, Boostandoot E, Spano JP et al. Temsirolimus-induced glomer-
Am J Physiol Renal Physiol 2008; 294: F93–F99 || ulopathy. Oncology 2009; 76: 170–172
101. Brosnan EM, Weickhardt AJ, Lu X et al. Drug-induced reduction in esti- || 125. Chanan-Khan A, Cramer P, Demirkan F et al.; HELIOS investigators.
||
mated glomerular filtration rate in patients with ALK-positive non-small || Ibrutinib combined with bendamustine and rituximab compared with pla-
cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2014; || cebo, bendamustine, and rituximab for previously treated chronic lympho-
120: 664–674 || cytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised,
102. Camidge DR, Brosnan EM, DeSilva C et al. Crizotinib effects on creatinine
|| double-blind, phase 3 study. Lancet Oncol 2016; 17: 200–211
||
and non-creatinine-based measures of glomerular filtration rate. J Thorac || 126. Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the
Oncol 2014; 9: 1634–1637 || administration of rituximab in lymphoproliferative disorders: high-grade
103. Gastaud L, Ambrosetti D, Otto J et al. Acute kidney injury following crizo- || non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Am J
tinib administration for non-small-cell lung carcinoma. Lung Cancer 2013;
|| Hematol 1999; 62: 247–250
||
82: 362–364 || 127. Jensen M, Winkler U, Manzke O et al. Rapid tumor lysis in a patient with
104. Valcovici M, Andrica F, Serban C et al. Cardiotoxicity of anthracycline || B-cell chronic lymphocytic leukemia and lymphocytosis treated with an
therapy: current perspectives. Arch Med Sci 2016; 12: 428–435 || anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab). Ann Hematol
105. Jensen BV. Cardiotoxic consequences of anthracycline-containing therapy
|| 1998; 77: 89–91
||
in patients with breast cancer. Semin Oncol 2006; 33 (Suppl 15): S15–S21 || 128. Guleria AS, Yang JC, Topalian SL et al. Renal dysfunction associated with
106. Huszno J, Badora A, Nowara E. The influence of steroid receptor status on || the administration of high-dose interleukin-2 in 199 consecutive patients
the cardiotoxicity risk in HER2-positive breast cancer patients receiving || with metastatic melanoma or renal carcinoma. J Clin Oncol 1994; 12:
trastuzumab. Arch Med Sci 2015; 11: 371–377
|| 2714–2722
||
107. Russo G, Cioffi G, Di Lenarda A et al. Role of renal function on the devel- || 129. Selby P, Kohn J, Raymond J et al. Nephrotic syndrome during treatment
opment of cardiotoxicity associated with trastuzumab-based adjuvant che- || with interferon. Br Med J (Clin Res Ed) 1985; 290: 1180
motherapy for early breast cancer. Intern Emerg Med 2012; 7: 439–446 || 130. Zuber J, Martinez F, Droz D et al. Alpha-interferon-associated thrombotic
||
108. Albini A, Donatelli F, Focaccetti C et al. Renal dysfunction and increased || microangiopathy: a clinicopathologic study of 8 patients and review of the
risk of cardiotoxicity with trastuzumab therapy: a new challenge in cardio- || literature. Medicine (Baltimore) 2002; 81: 321–331
oncology. Intern Emerg Med 2012; 7: 399–401 || 131. Domschke C, Schuetz F. Side effects of bone-targeted therapies in advanced
109. Untch M, Muscholl M, Tjulandin S et al. First-line trastuzumab plus epiru-
|| breast cancer. Breast Care (Basel) 2014; 9: 332–336
||
bicin and cyclophosphamide therapy in patients with human epidermal || 132. Edwards BJ, Usmani S, Raisch DW et al. Acute kidney injury and
growth factor receptor 2-positive metastatic breast cancer: cardiac safety || bisphosphonate use in cancer: a report from the research on adverse drug
and efficacy data from the herceptin, cyclophosphamide and epirubicin || events and reports (RADAR) project. J Oncol Pract 2013; 9: 101–106
(HERCULES) trial. J Clin Oncol 2010; 28: 1473–1480
|| 133. Hu MI, Glezerman IG, Leboulleux S et al. Denosumab for treatment
||
110. Topalian SL, Hodi FS, Brahmer JR et al. Safety, activity, and immune corre- || of hypercalcemia of malignancy. J Clin Endocrinol Metab 2014; 99:
lates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–2454 || 3144–3152
111. Brahmer JR, Drake CG, Wollner I et al. Phase I study of single-agent anti- || 134. Lipton A, Fizazi K, Stopeck AT et al. Superiority of denosumab to
programmed death-1 (MDX-1106) in refractory solid tumors: safety, clini-
|| zoledronic acid for prevention of skeletal-related events: a combined
||
cal activity, pharmacodynamics, and immunologic correlates. J Clin Oncol || analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer 2012; 48:
2010; 28: 3167–3175 || 3082–3092
112. Hamid O, Robert C, Daud A et al. Safety and tumor responses with lam- || 135. Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zoledronic
||
brolizumab (anti-PD-1) in melanoma. N Engl J Med 2013; 369: 34–44 || acid for the treatment of bone metastases in patients with advanced breast
113. Hofmann L, Forschner A, Loquai C et al. Cutaneous, gastrointestinal, hep- || cancer: a randomized, double-blind study. J Clin Oncol 2010; 28:
atic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer || 5132–5139
2016; 68: 287–291
|| 136. Body JJ, Bone HG, de Boer RH et al. Hypocalcaemia in patients with meta-
||
114. Shirali AC, Perazella MA, Gettinger S. Association of acute interstitial || static bone disease treated with denosumab. Eur J Cancer 2015; 51:
nephritis with programmed cell death 1 inhibitor therapy in lung cancer || 1812–1821
patients. Am J Kidney Dis 2016; 68: 287–291 || 137. Russell RG, Watts NB, Ebetino FH et al. Mechanisms of action of
115. Izzedine H, Gueutin V, Gharbi C et al. Kidney injuries related to ipilimu-
|| bisphosphonates: similarities and differences and their potential influence
||
116.
mab. Invest New Drugs 2014; 32: 769–773
Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus
||| on clinical efficacy. Osteoporos Int 2008; 19: 733–759
138. Drake MT, Clarke BL, Khosla S. Bisphosphonates: mechanism of action
||
nephritis. N Engl J Med 2009; 361: 211–212 || and role in clinical practice. Mayo Clin Proc 2008; 83: 1032

Chemotherapy-associated nephrotoxicity 935

139. Markowitz GS, Appel GB, Fine PL et al. Collapsing focal segmental glo- ||
merulosclerosis following treatment with high-dose pamidronate. J Am Soc ||
Nephrol 2001; 12: 1164–1172 ||
140. Sauter M, Jülg B, Porubsky S et al. Nephrotic-range proteinuria following ||
pamidronate therapy in a patient with metastatic breast cancer: mitochondrial
||
||
toxicity as a pathogenetic concept? Am J Kidney Dis 2006; 47: 1075–1080 ||
141. Kunin M, Kopolovic J, Avigdor A et al. Collapsing glomerulopathy ||
induced by long-term treatment with standard-dose pamidronate in a ||
||
myeloma patient. Nephrol Dial Transplant 2004; 19: 723–726 ||
142. Jia N, Cormack FC, Xie B et al. Collapsing focal segmental glomeruloscle- ||
rosis following long-term treatment with oral ibandronate: case report and ||
review of literature. BMC Cancer 2015; 15: 535
||
||
143. Gokden N, Zangari M, Elici F et al. Potential effect of zoledronate therapy
in heavy proteinuria. Clin Nephrol 2007; 67: 263–265
144. Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of
zoledronic acid compared with pamidronate disodium in the treatment of
skeletal complications in patients with advanced multiple myeloma or
breast carcinoma: a randomized, double-blind, multicenter, comparative
trial. Cancer 2003; 98: 1735–1744
145. Barri YM, Munshi NC, Sukumalchantra S et al. Podocyte injury associated
glomerulopathies induced by pamidronate. Kidney Int 2004; 65: 634–641
146. Markowitz GS, Fine PL, Stack JI et al. Toxic acute tubular necrosis follow-
ing treatment with zoledronate (Zometa). Kidney Int 2003; 64: 281–289
147. Diel IJ. Bisphosphonates in breast cancer patients with bone metastases.
Breast Care 2010; 5: 306–311
148. Bodmer M, Amico P, Mihatsch MJ et al. Focal segmental glomerulosclero-
sis associated with long-term treatment with zoledronate in a myeloma
patient. Nephrol Dial Transplant 2007; 22: 2366–2370
149. Vielhauer V, Mayadas TN. Functions of TNF and its receptors in renal dis-
ease: distinct roles in inflammatory tissue injury and immune regulation.
Semin Nephrol 2007; 27: 286–308
|| 150. Jhaveri KD, Sakhiya V, Wanchoo R et al. Renal effects of novel anticancer
|| targeted therapies: a review of the Food and Drug Administration Adverse
|| Event Reporting System. Kidney Int 2016; 90: 706–707
||
||
|| Received: 1.5.2016; Editorial decision: 10.8.2016
||
||
||
|

Downloaded from https://academic.oup.com/ndt/article/32/6/924/3059468 by guest on 19 May 2021

Nephrol Dial Transplant (2017) 32: 936–942
doi: 10.1093/ndt/gfw382
Advance Access publication 26 December 2016

Renal effects of immune checkpoint inhibitors

Hassan Izzedine1, Christine Mateus2, Céline Boutros2, Caroline Robert2, Philippe Rouvier3, Zahir Amoura4
and Alexis Mathian4
1
Department of Nephrology, Monceau Park International Clinic Paris, France, 2Department of Oncology, Gustave Roussy Institute, Villejuif,
France, 3Department of Pathology, Pitie-Salpetriere Hospital, Paris, France and 4Department of Internal Medicine 2, Pitie-Salpetriere Hospital,
Paris, France

Correspondence and offprint requests to: Hassan Izzedine; E-mail: hassan.izzedine@clinique-monceau.com

|| Keywords: checkpoint blockade, immunotherapy, ipilimu-

ABSTRACT || mab, nivolumab, pembrolizumab
||
Recent advances in immune checkpoint inhibitor (ICPI) devel-
||
|| Immunotherapy has long been part of the standard treatment
opment have led to major improvements in oncology patient ||
outcomes. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and
|| for early-stage cancers. The most well-known treatments
|| include the intravesical bacillus Calmette–Guérin vaccine for
programmed cell death protein 1 (PD-1) are two essential ||
immune checkpoint receptors. Ipilimumab and tremelimumab
|| non-muscle-invasive bladder cancer and topical imiquimod for
|| superficial basal and squamous cell skin carcinomas. In addi-
(anti-CTLA-4-blocking antibodies) and pembrolizumab and ||
nivolumab (antibodies targeting PD-1 receptors) have already
|| tion, high-dose interleukin-2 can also be used for the metastatic
||
been approved by US Food and Drug Administration in several || stage in renal cell carcinoma and melanoma [1–3].
|| Over the past decade, the ability of cancer cells to evade
malignancies. Two different forms of ICPI-induced renal dam- ||
age have been identified, including acute (granulomatous) tubu- || immune destruction has been recognized as one of the hall-
|| marks of tumour pathogenesis [4]. This understanding has fav-
lointerstitial nephritis and immune complex glomerulonephri- ||
tis. The observed acute renal damage can be reversed upon ICPI || oured the development of novel therapeutic agents that can
|| activate anti-tumour immune responses or reverse immuno-
drug discontinuation and renal function can recover back to ||
suppressive mechanisms through which tumours escape
normal following the introduction of systemic corticosteroid |||
treatment. Any delay in treating this complication could result || immune-mediated rejection [4].
|| Nowadays, blockade of immune checkpoints has been iden-
in definitive and irreversible renal injury. ||
| tified as the most effective immunotherapy approach used to

C The Author 2016. Published by Oxford University Press

V 936
on behalf of ERA-EDTA. All rights reserved.