Clinical Practice: Review Article

Nephron 2023;147:65–77 Received: January 18, 2022

Accepted: April 24, 2022
DOI: 10.1159/000525029 Published online: June 17, 2022

Onconephrology: Update in Anticancer

Drug-Related Nephrotoxicity
Clara García-Carro a Juliana Draibe b María José Soler c
aNephrology
Department, San Carlos Clinical University Hospital, Madrid, Spain; bNephrology Department, Bellvitge
Hospital, Hospitalet Llobregat, Barcelona, Spain; cNephrology Department, Vall d’Hebron University Hospital,

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Vall d’Hebron Institute of Research, CSUR National unit of Expertise for Complex Glomerular diseases of Spain,
Barcelona, Spain

Keywords therapy. In addition, strategies for prevention and manage-

Onconephrology · Immunotherapy · Chemotherapy · ment recommendations in patients with malignancies and
Kidney injury · Cancer kidney disease will also be addressed.
© 2022 S. Karger AG, Basel

Abstract
The relation that connects cancer and renal damage is bidi-
rectional and this renal damage worsens quality of life and
increases morbidity in high-complexity patients such as pa-
tients with cancer and kidney injury. Strikingly, in the last
decade, the treatment of advanced cancer has clearly ad-
vanced in terms of new therapeutic strategies with the abil-
ity to transform the advanced metastatic cancer in a chronic
condition. In this new era of cancer therapies, cancer treat-
ment including conventional chemotherapy, targeted can-
cer agents and immunotherapies among others are signifi-
cantly associated with kidney injury. Renal toxicity that is
currently seen in onconephrology departments is in part re-
lated to the new therapies such as immunotherapy, and to
the prolonged survival achieved at the expense of increasing
therapy lines, and a combination of different drugs. In this
review, we will discuss in a practical way, nephrotoxicity
caused by the main oncospecific treatments such as classical
chemotherapy agents, targeted therapies, and immuno-
Introduction
Cancer is one of the leading causes of death and in-
creased morbidity in the world [1]. In the last decade, new
therapies have changed life expectancy in patients with
malignancy, however, as well as classical chemotherapy
agents, they are not free of adverse events. Renal function
impairment and nephrotoxicity are one of the major lim-
itations of cancer treatment. The relation that connects
cancer and renal damage is bidirectional and this renal
damage increases mortality and morbidity in patients
with cancer. Patients with cancer who develop acute kid-
ney injury (AKI) during oncologic treatments and pa-
tients with chronic kidney disease (CKD) who develop
cancer are frequently medicated with suboptimal thera-
Clara García-Carro and Juliana Draibe contributed equally to this
work.

Karger@karger.com © 2022 S. Karger AG, Basel Correspondence to:

www.karger.com/nef María José Soler, mjsoler01 @ gmail.com
Table 1. Conventional chemotherapy and nephrotoxicity

Medication Nephrotoxicity Mechanism of nephrotoxicity Prevention and management

recommendations

Platinum compounds ATI Direct tubular toxicity Hydration

(cisplatin, carboplatin, Hypomagnesemia Magnesium supplementation
oxaliplatin) Nephrogenic diabetes insipidus Forced diuresis with mannitol
Proximal tubulopathy
TMA
Ifosfamide ATI Mitochondrial tubular toxicity No current strategy for preventing
Proximal tubulopathy ifosfamide nephrotoxicity
CKD NAC: some beneficial effects
Pemetrexed ATI Antifolate effect that impairs DNA Leucovorin therapy
Proximal tubulopathy and RNA
Nephrogenic diabetes insipidus

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Methotrexate ATI Direct tubular toxicity Volume filling/urine alkalization (pH >7.5)
Crystalline nephropathy Induction of oxygen free radical Leucovorin therapy
formation Prolonged hemodialysis
Glucarpidase
Gemcitabine TMA Endothelial injury Eculizumab
Microvascular thrombosis
Mitomycin C TMA Endothelial injury Drug discontinuation
Microvascular thrombosis Supportive care

ATI, acute tubular Injury; CKD, chronic kidney injury; TMA, thrombotic microangiopathy; NAC, N-acetylcysteine.

peutic choices because of the lack of randomized clinical
trials in population with impaired renal function [2, 3],
this fact has a probably deleterious impact in survival out-
comes. With the aim to identify, treat, and, if possible,
prevent kidney damage in patients with cancer, the sub-
specialist of onconephrology has been created in the last
years [4].
New oncospecific therapies have achieved dramatical-
ly better survival outcomes in different types of cancer;
however, renal toxicity seems not to be decreasing. Renal
toxicity that is nowadays seen in onconephrology depart-
ments is in part related to the new therapies such as im-
munotherapy, and to the prolonged survival achieved at
the expense of increasing therapy lines, and a combina-
tion of different drugs. The admission of elderly patients
with many comorbidities, such as hypertension (HTN) or
diabetes mellitus, and baseline renal dysfunction, to on-
cospecific and potentially nephrotoxic treatments, could
also in part play an important role in the development of
kidney toxicity.
Currently, in this new onconephrology scenario, on-
cologic patients with renal disease are commonly treated
by nephrology specialists. With the aim to avoid CKD
and/or renal dysfunction progression in patients with po-
tentially curable malignancies, nephrologists should be
able to manage renal toxicities of oncospecific drugs. In
this review, we will discuss in a practical way, nephrotox-
icity caused by main oncospecific treatments: classical
chemotherapy agents, targeted therapies, and immuno-
therapy. Furthermore, prevention and management rec-
ommendations in patients with malignancies and kidney
disease are also addressed.
Conventional Chemotherapy
As it is already known, conventional chemotherapy
has been classically associated with AKI; caused primar-
ily by acute tubular toxicity, acute tubulointerstitial ne-
phritis (ATIN), and different glomerulonephritis [5–7].
It is frequently related with drug dosage and treatment
duration. Briefly, we will assess the more important che-
motherapeutic agents associated with renal toxicity (see
Table 1).

66 Nephron 2023;147:65–77 García-Carro/Draibe/Soler

DOI: 10.1159/000525029

Fig. 1. Glomerular and tubular patterns of anticancer drug-related kidney injury.
Platinum Compounds (Cisplatin, Carboplatin,
Oxaliplatin)
Cisplatin is a widely used and highly effective cancer
chemotherapeutic agent. It has been mainly related to re-
versible AKI approximately 3–5 days after drug exposure,
although repeated doses (>100 mg/m2) may cause a per-
manent kidney injury [5–7]. Besides AKI, cisplatin has
been also associated with hypomagnesemia [8], nephro-
genic diabetes insipidus [9], proximal tubulopathy [10],
and less frequently with thrombotic microangiopathy
[11] (see Fig. 1). Appropriate knowledge regarding the
pharmacokinetics and toxicological profile of cisplatin
may help physicians prevent renal toxicity. Accurate hy-
dration remains the main fundamental strategy for re-
ducing the risk of cisplatin-induced nephrotoxicity. In-
terestingly, magnesium supplementation may have a role
as a nephroprotective agent, and forced diuresis with
mannitol may be appropriate in some patients receiving
cisplatin [12].
Carboplatin and oxaliplatin, are the second and third
generation of platinum agents, respectively. They are less
Anticancer Drug-Related Nephrotoxicity
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nephrotoxic than cisplatin but can still cause AKI in pa-
tients with lower albumin (higher unbound fraction of
platinum resulting in greater peak plasma concentra-
tions), preexisting kidney damage, and concurrent use of
nephrotoxic medications (like nonsteroidal anti-inflam-
matory drugs NSAIDS, iodinated contrast) [13].
Ifosfamide
Ifosfamide is an alkylating drug; it is often combined
with cisplatin for the treatment of sarcomas, testicular tu-
mors, and some refractory lymphomas. Its renal toxicity
has been associated with proximal tubular dysfunction
(Fanconi Syndrome) and AKI, especially when combined
with platinum drugs, and can progress to CKD [14, 15].
When ATN occurs in the context of ifosfamide treatment,
a special histological feature might be found by optical
microscope the presence of karyomegalic cells. Karyome-
galic changes in tubular epithelial cells result from aber-
rant cell division related to exposure to the toxic ifos-
famide, secondarily inducing interstitial inflammation
[15]. In this setting, Akilesh et al. [16] described intersti-
Nephron 2023;147:65–77 67
DOI: 10.1159/000525029
tial fibrosis and tubular atrophy in patients treated with
ifosfamide, whereas several biopsies also contained inter-
stitial inflammation.
Pemetrexed
Pemetrexed is a methotrexate analog that inhibits 3
enzymes involved in folate metabolism and thus pu-
rine/pyrimidine production needed for DNA synthesis.
Regarding its renal toxicity, it has been associated with
AKI, proximal tubulopathy, and nephrogenic diabetes
insipidus. Renal histology reveals ATN with mild-to-
moderate interstitial fibrosis and, in a minority of cases,
mild interstitial inflammation [17, 18]. Pemetrexed is
currently contraindicated when the estimated creati-
nine clearance is <45 mL/min because of fatal toxicities
in patients with renal impairment [19]. In that line, in-
novative interventions as leucovorin therapy, used for
methotrexate toxicity, are needed to allow a safe treat-
ment [20].
Methotrexate
As permetrexed, methotrexate inhibits folate metabo-
lism, specifically dihydrofolate reductase. Methotrexate
precipitation and metabolites within tubular lumen lead
to AKI and crystalline nephropathy [7, 21]. After AKI oc-
curs, the excretion of the drug is reduced and the patient
can develop systemic toxicity. Several strategies as high-
dose of leucovorin therapy (a folate compound), pro-
longed hemodialysis [22] (daily for several days, to avoid
rebound), or glucarpidase (an enzyme that inactivates the
drug) can be used when AKI and severe systemic toxici-
ties developed [23].
Gemcitabine
Thrombotic microangioapthy (TMA) is a rare compli-
cation related with gemcitabine with a high mortality
rate. It is characterized by microangiopathic hemolytic
anemia, thrombocytopenia, and end-organ damage. In
the largest case series of TMA related to gemcitabine, au-
thors describe new-onset or exacerbated HTN and edema
as early signs of TMA, suggesting that in front of these
clinical symptoms close monitoring may be useful [24].
A kidney biopsy can reveal endothelial cell swelling, fi-
brin thrombi within capillary loops and arterioles, me-
sangiolysis and thickened arterioles, and glomerular cap-
illaries [25]. Some case reports suggest that complement
inhibition with eculizumab could be a reasonable therapy
when plasmapheresis failed in patients with gemcitabine-
associated TMA [26].
68 Nephron 2023;147:65–77
DOI: 10.1159/000525029
Mitomycin C
Mitomycin C is also related with dose-dependent
TMA. Drug discontinuation and supportive care are in-
dicated in that case, as plasmapheresis is ineffective [27].
Gemcitabine, mitomycin C, and platinum compounds
were categorized by Izzedine and Perazella [28] as “Type
I” cancer drug TMA and anti-vascular endothelial growth
factor (VEGF) agents (discussed below) as “Type II” can-
cer drug TMA, on the basis of their different mechanisms
of kidney injury and outcomes. In type I, endothelial in-
jury and/or microvascular thrombosis are involved in the
pathogenesis; it has been related to cumulative drug dose,
may present many months after beginning or ending
treatment, and is refractory to therapy. In relation to renal
histology, fibrin thrombi are often found in glomerular
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and arteriolar compartments, whereas in “Type II” only
glomerular thrombi are seen.
Target Cancer Agents
Several families of transmembrane receptors or intra-
cellular tyrosine kinase inhibitors (TKIs) participate in
the tumor growth when aberrant activation is present.
The main strategies of inhibition include inhibitory anti-
bodies (bevacizumab: anti-VEGF, cetuximab: anti-epi-
dermal growth factor receptor [EGFR]) or small molecu-
lar TKIs (gefitinib/erlotinib: anti-EGFR, sunitinib: anti-
ALK) [29] (see Table 2).
Anti-VEGF (Aflibercept, Bevacizumab)
The hypothesis that some kind of tumor growth is de-
pendent on angiogenesis has been the rationale to devel-
op antiangiogenic drugs. Antiangiogenic drugs can target
the VEGF itself (bevacizumab, aflibercept), block the
VEGF receptor (ramucirumab), or be TKIs of the VEGF
receptor [30]. TKIs of VEGF receptor will be reviewed in
the next section.
Bevacizumab and aflibercept are increasingly applied
to treat malignancies like metastatic or recurrent colorec-
tal, non-small cell lung, breast, and renal cell cancers and
ramucirumab has been approved as a second line therapy
for gastric, non-small-cell lung, and metastatic colorectal
cancers [31]. Despite their mechanisms of action are not
the same, the three drugs inhibit endothelial cell prolif-
eration and vessel development and can cause HTN,
asymptomatic albuminuria, nephrotic syndrome, and
TMA. VEGF is mainly expressed in podocytes and re-
quired to maintain the integrity of glomerular endothe-
lial function and glomerular filtration barrier. The regula-
García-Carro/Draibe/Soler
Table 2. Target cancer agents and nephrotoxicity

Medication Mechanism of action Nephrotoxicity Prevention and management

recommendations

EGFR pathway EGFR-TKI inhibitors (erlotinib, gefitinib) MCD Drug discontinuation

inhibitors Membranous nephropathy
anti-EGFR receptor Hypomagnesemia Drug discontinuation
Antibodies (cetuximab, panitumumab) Hypokalemia
Nephrotic syndrome
IgA glomerulonephritis
Anaplastic Crizotinib AKI (NTA and ATIN) Drug discontinuation
lymphoma kinase ALK TKI inhibitor Formation or increase of renal cysts
inhibitors c-MET, ROS1 inhibitor Hypophosphatemia
BRAF inhibitors Inhibitors of mutant BRAF (vemurafenib, Fanconi syndrome Drug discontinuation
debrafenib) Hypophosphatemia

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Hyponatremia
Hypokalemia
AKI (NTA and ATIN)
VEGF pathway VEGF-TKI inhibitors (axitinib, pazopanib, FSGS/MCD (sunitinib/sorafenib) Drug discontinuation
inhibitors sorafenib, regorafenib, sunitinib) TMA (sunitinib) Angiotensin-converting
NTA (sunitinib/sorafenib) enzyme inhibitor
Hypophosphatemia, hypocalcemia,
hyponatremia, hypokalemia (regorafenib)
Anti- VEGF receptor antibodies TMA Drug discontinuation
Bevacizumab: mAb against VEGFA. IgA nephropathy Angiotensin-converting
Aflibercept: Recombinant fusion protein ANCA glomerulonephritis enzyme inhibitor
(VEGF trap) Diabetic nephropathy
Ramucirumab: mAb against VEGFR2 FSGS/MCD
Membranous nephropathy
Bcr-abl TKIs 1st generation: Nilotinib, imatinib Hypophosphatemia Monitoring of renal function
(Bcr-abl TKI) ATP-competitive TKI Reversible decrease in GFR Dose reduction when
Src family kinases inhibition AKI (TLS) decrease GFR
NTA (imatinib)
2nd generation: dasatinib Proteinuria, nephrotic syndrome: Dose reduction o drug
Platelet-derived growth factor receptor (dasatinib) discontinuation
Tyrosine kinase receptor KIT (CD117) NTA (ibrutinib) Change 1st generation Bcr-
VEGF inhibition abl tyrosine kinase inhibitors
Ibrutinib

EGFR, epidermal growth factor receptor, TKI: EGFR-tyrosine kinase inhibitors; 2. BRAF, encoding gene human protein B-Raf; VEGF,
vascular endothelial growth factor; MCD, minimal change disease; FSGF, focal segmental glomerulosclerosis; AKI, acute kidney injury; ATN,
acute tubular necrosis; NTIA, acute tubulointerstitial nephritis; TMA, thrombotic microangiopathy; CKD, chronic kidney injury; TLS, tumor
lysis syndrome.

tion of susceptibility to VEGF inhibition is not well un-
derstood, and it is unknown why some patients tolerate
long-term anti-VEGF therapies and others develop TMA,
mainly limited to the kidney.
The less severe renal adverse event associated with an-
ti-VEGF is HTN, which appears in 16%–43% of patients.
Angiotensin-converting enzyme inhibitors (ACEIs) or
angiotensin receptor blockers (ARB) are the first-line
therapy and calcium channel blockers are the second
choice. Diuretic agents can also be added. Normally,
blood pressure can be controlled and it is not necessary
to stop the cancer treatment [30, 32]. All degree of pro-
teinuria is more common in patients on aflibercept than
in those on bevacizumab (33.9% vs. 13.3%) and it is as-

Anticancer Drug-Related Nephrotoxicity Nephron 2023;147:65–77 69

DOI: 10.1159/000525029
sociated to the disruption of the glomerular filtration bar-
rier. Treatment can be continued in most cases involving
non-nephrotic-range proteinuria, and HTN and protein-
uria can be aggressively managed with ACEIs or ARBs.
Risk factors for the development of proteinuria are base-
line elevated systolic blood pressure, number of cycles of
anti-VEGF drug, and previous use of calcium channel
blockers [33]. If possible, kidney biopsy is recommended
when proteinuria appears, but even more when it is over
3 g per day or associated to AKI, since histological find-
ings could influence prognosis and treatment options.
Anti-VEGF therapies have been related with minimal
change disease and focal segmental glomerulosclerosis
(FSGS), but the most common histologic pattern is TMA.
Anti-VEGF-associated TMA, as well as nephrotic range
proteinuria, are considered a reason to discontinue the
culprit drug. Renal response to discontinuation of the of-
fending agent is normally good with no need of other spe-
cific treatment [30, 32]. Recently, some case series of bev-
acizumab-associated TMA treated with eculizumab have
been reported, suggesting that complement blockade
should be an option for patients without response to the
classical management [34, 35].
TKIs (Axitinib, Pazopanib, Sorafenib, Regorafenib,
Sunitinib)
Decreased GFR has been reported during therapy with
axitinib, sunitinib, and sorafenib, although renal failure is
rare. TKIs are also related with TMA. In particular, suni-
tinib in a case report of 5 patients has been associated with
AKI, eosinophilia, and/or nephrotic syndrome, and/or
TMA; although none were biopsied [36]. NTIA has been
also diagnosed in a biopsy-proven cases related with suni-
tinib and sorafenib [37, 38]. Besides, small series and case
reports related, these two drugs with minimal change,
FSGS, and immune complex deposition have been pub-
lished [39, 40]. Regorafenib has been associated with sev-
eral electrolyte abnormalities, including hypophosphate-
mia, hypocalcemia, hyponatremia, and hypokalemia
[41].
BRAF Inhibitors (Dabrafenib, Vemurafenib)
Many melanomas and other tumors cause point muta-
tions in the serine-threonine kinase BRAF. Dabrafenib
and vemurafenib are the two approved inhibitors of mu-
tant BRAF for use in melanoma. They have been related
with AKI and some electrolytes disorders as Fanconi syn-
drome, hypophosphatemia, hyponatremia, and hypoka-
lemia [42]. The mechanism of kidney injury is unknown;
however, BRAF inhibitors interfere with the downstream
70 Nephron 2023;147:65–77
DOI: 10.1159/000525029
mitogen-activated protein kinase pathway, increasing is-
chemic tubular damage. Although there is a paucity of
renal biopsy, it seems that this drug causes mainly a tubu-
lar injury, as ATN and ATIN, reported in some case re-
ports. In these cases, drug discontinuation seems to lead
the recovery of kidney function [43].
ALK Inhibitors (Crizotinib)
Crizotinib is approved for non-small cell lung cancer,
inhibiting the ALK, MET, and ROS1 kinases. Renal tox-
icities include AKI (NTA and ATIN) and the formation
or increase of renal cysts during treatment for lung cancer
[44]. Schnell et al. [45] reviewed 272 patients treated with
this drug in clinical trials and found new renal cysts (9%)
or increase in the size of renal cysts (2%) of treated pa-
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tients [45]. Furthermore, reductions in GFR have been
observed in patients who underwent this therapy.
EGFR Inhibitors (Cetuximab, Erlotinib, Gefitinib,
Panitumumab)
Inhibition of EGFR, that results in phosphorylation of
the receptor tyrosine kinase modulating cell differentia-
tion, proliferation, and survival; is crucial for the treat-
ment of some cancers such as non-small cell lung cancer.
EGFR inhibitors have been associated with electrolyte
disorders; mainly hypomagnesemia; but also hypophos-
phatemia, and hypokalemia. Increased renal magnesium
has been found in 37% of patients, which resolves with
therapy discontinuation [46]. Cetuximab has also been
associated with a single case of IgA glomerulonephritis
[47] and nephrotic syndrome [48].
Bcr-Abl TKIs
Bcr-Abl TKIs are the first-line therapy in chronic my-
elogenous leukemia, caused by chromosomic abnormali-
ties resulting in the so-called Philadelphia chromosome
in more than 90% of patients. The presence of the chime-
ric oncogene BCR-Abl constitutes an active BRC-Abl ty-
rosine kinase, a pathogenic factor of the disease. These
inhibitors are imatinib, dasatinib, nilotinib, and pona-
tinib [49]. Imatinib has been related to episodes of AKI in
7% and also to CKD. The decrease in the glomerular fil-
tration rate has been associated with the treatment dura-
tion [50]. AKI could appear as a part of a tumor lysis syn-
drome (TLS) and drive to tubular damage. Interestingly,
acute tubular necrosis has been described as the histo-
logic lesion in a patient on imatinib treatment who devel-
oped AKI and required renal replacement therapy [51].
Proteinuria could also appear in patients under imatinib
treatment, often related de VEGF inhibition. Data about
García-Carro/Draibe/Soler
AKI related to nilotinib or ponatinib are scarce, but both
cause HTN in 10% and 50% of patients, respectively. Hy-
pophosphatemia is also common in BCR-Abl TKIs treat-
ments, because they inhibit phosphorus tubular reab-
sorption.
Ibrutinib inhibits the Bruton tyrosine kinase and is
commonly used as treatment of chronic lymphocytic leu-
kemia. It has been related to HTN and also to TLS in a few
cases. Recently, two cases of biopsy-proven acute tubular
injury secondary to ibrutinib have been published, and
the authors review adverse events related to this drug: a
total of 25% from more than 600 adverse events were re-
ported as AKI [52, 53].
Cyclin-Dependent Kinases 4/6 Inhibitors and
Poly(ADP-Ribose) Polymerase Inhibitors
Cyclin-dependent kinases (CDK) inhibitors targeting
CDK4 and CDK6 are currently commonly used in hor-
mone receptor-positive breast cancer, mainly in advanced
stages [54]. Abemaciclib and other inhibitors of CDK 4/6
have been associated with reversible increases in serum
creatinine (SCr) levels of ∼15%–40% over baseline. Data
of a recent in vitro study of abemaciclib renal effect
showed that this increase is caused by inhibition of renal
transporters and CDK4/6 inhibitors seem not to affect
renal function when assessed by measured GFR, or mod-
ify the concentrations of urinary biomarkers of renal in-
jury such as NGAL or KIM-1. Patients under abemaciclib
will experience a mild (∼10%–40%) reversible increase in
SCr due to renal transport inhibition. The increase in SCr
following may be higher in patients with CKD. When
clinically indicated, alternative measurements of renal
function different from creatinine-derived EGFR should
be used in patients taking these drugs [55].
Olaparib, niraparib, rucaparib, and talazoparib are
poly (ADP-ribose) polymerase (PARP) inhibitors that
are also used in gynecological cancer: both ovary and
breast cancer [56, 57]. Despite their mechanism of action
is not similar to CDK inhibitors, this group of drugs could
also cause inhibition of renal transporters leading to a re-
versible and dose-dependent increase in SCr not affecting
GFR, since the median cystatin C-derived EGFR was
comparable before/off treatment and during treatment
with olaparib in a study by Bruin et al. [58]. As with CKD
inhibitors, the use of the creatinine-derived EGFR can
give an underestimation of GFR in patients taking olapa-
rib. Therefore, an alternative renal marker should be used
to accurately calculate GFR in these patients. Interesting-
ly, PARP inhibitors, and especially niraparib, have been
related to any-grade HTN, any-grade HTN secondary to
Anticancer Drug-Related Nephrotoxicity
inhibition of dopamine, norepinephrine, and serotonin
reuptake. Patients on niraparib therapy should have their
blood pressure monitored at least monthly for the first
year of treatment. If HTN is developed, it should be man-
aged with standard antihypertensive drugs and, if neces-
sary, adjusting PARP inhibitor dosing [59].
BCL-2 Inhibitor (Venetoclax)
The members of the B-cell leukemia/lymphoma-2
(BCL-2) family of proteins are key regulators of the in-
trinsic apoptotic pathway; dysregulation of this pathway
leads to the pathologic survival of cancer cells [60]. Vene-
toclax is a BCL-2 inhibitor approved for chronic lympho-
cytic leukemia and acute myeloid leukemia [60, 61].
Venetoclax can lead to rapid TLS in CLL patients and, in
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order to minimize this adverse effect, a weekly dose ramp-
up is recommended [62]. Furthermore, a recently pub-
lished case series suggested that TLS prophylaxis with al-
lopurinol >72 h prior to venetoclax initiation is beneficial
[63].
Proteasome Inhibitors
Proteasome inhibitors (PIs) are a cornerstone for the
treatment of multiple myeloma (MM), a plasma cell dis-
order characterized by abnormal proliferation of plasma
cells resulting in overproduction of paraprotein that rep-
resents 10% of hematological malignancies. First ap-
proved PI was bortezomib, and then carfilzomib and ixa-
zomib [64]. There are increasing reports of TMA in as-
sociation with PI exposure. It is interesting to mention
that prior to the use of PIs, the incidence of TMA in pa-
tients with MM was much lower, most frequently associ-
ated with autologous stem-cell transplant and that there
are no reported cases of PI-related TMA in patients with
lymphoma, where PI are also used. Thus, MM itself could
be a risk factor for PI-induced TMA. The morbidity and
mortality of PI-related TMA are notable and for that rea-
son, clinical vigilance is required for early detection and
intervention. TMA is not limited to the kidney and
supportive treatment, including renal replacement thera-
pies and blood transfusions, is needed, as well as a cessa-
tion of PI and any other offending agent. TMA seems to
be more frequent in patients on carfilzomib than in those
on bortezomib according to the literature [65].
Nephron 2023;147:65–77 71
DOI: 10.1159/000525029
Table 3. Cancer immunotherapies and nephrotoxicity

Medication Nephrotoxicity Mechanism of nephrotoxicity Prevention and

management
recommendations

IFN MCD/FSGS Direct effects of IFN on the podocyte Drug discontinuation

TMA Indirect effects via altered cytokine milieu Steroids (MCD/FSGS)
Damage microvascular endothelial cells by
inducing apoptosis in a dose-dependent manner
Interleukin-2 Hemodynamic AKI Capillary leak syndrome leading to AKI Volume filling
ATI
CAR-T Hemodynamic AKI CRS Previous chemotherapy/
ATI steroids
TLS Supportive treatment
Anti-IL-6: Tocilizumab

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Immune checkpoint ATIN Formation of new or reactivated T cells against CPI withdrawal
inhibitors (CTLA-4 ATI tumor antigens that cross-react with kidney Steroids
inhibitors, PD-1 Lupus-like glomerulonephritis antigens
inhibitors, PD-L1 Podocytopathies Loss of tolerance with reactivation of drug-specific
inhibitors) Necrotizing glomerulonephritis and T cell induced by ICI
vasculitis Increase in proinflammatory cytokines in kidney
C3 glomerulonephritis tissue
TMA Generation of autoantibodies against kidney
tissues

MCD, minimal change disease; FSGS, focal segmental glomerulosclerosis; TMA, thrombotic microangiopathy; ATI, acute tubular injury;
CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death protein 1; PD-L1, programmed death-ligand 1.

Cancer Immunotherapies drug discontinuation is favorable in published series and

Outcomes in advanced neoplasia’s have dramatically
changed over the last decades. The use of drugs that mod-
ulate the immune response instead of direct tumor target-
ing plays an important role in this improvement in On-
cology [66]. However, the goal of modifying immune re-
sponse has been linked to renal-related adverse effects
that could limit the potential use of these treatments (see
Table 3).
Interferons
Interferons (IFNs) are a group of pleiotropic cytokines
that play important roles in intercellular communication
during innate and acquired immune responses as a host
defensive response against viral and bacterial infections.
They have been proposed for different diseases, such as
hepatitis or multiple sclerosis, and they have also been
identified as oncospecific therapies. IFNs have been re-
lated to nephrotic syndrome and AKI secondary to mini-
mal change disease and FSGS [67]. Renal response to
steroids can also be used [68]. Black race and some APOL1
gene variants have been identified as risk factors for the
development of nephrotic syndrome under IFN treat-
ment [67, 69].
Interleukin-2
Interleukin-2 (IL2) has been used for years in the treat-
ment of renal-cell carcinoma and melanoma. High doses
are necessary and IL2 was initially associated with an im-
portant treatment-related mortality, that has substantial-
ly decreased as long as experience has been gained [70].
The main toxicity of IL2 is a capillary leak syndrome in
relation to an increased level of circulating cytokines.
This could drive to a hypovolemic/pre-renal AKI within
24–48 h after the drug infusion. Generally, AKI improves
after IL2 discontinuation and supportive care. However,
an acute tubular injury could be present if ischemia was
important and renal function recovery could be partial or
delayed [4].

72 Nephron 2023;147:65–77 García-Carro/Draibe/Soler

DOI: 10.1159/000525029
 Chimeric Antigen Receptor T-Cell
Chimeric antigen receptor (CAR) T-cell (CAR-T)
therapy has been a dramatic success in the treatment of
previously refractory hematologic malignancies. CAR-T
cells are host T cells submitted to engineering to express
receptors that recognize tumor antigens [71]. These ex
vivo modified T cells are able to target and directly de-
stroy cancer cells. The main adverse effect of CAR-T cells
therapy is cytokine release syndrome (CRS) in the onset
of immune activation [72], that could drive to hemody-
namic AKI or acute tubular injury in approximately 20%
of patients. The rapid onset of tumor destroy by CAR-T
cells could also promote a TLS and secondary renal in-
jury [71]. Acute tubular necrosis is related to a longer hos-
pital stay and a higher 60 days mortality [71]. Previous
chemotherapy and steroids are recommended with the
aim to reduce tumor size and to minimize CRS in patients
who will be under CAR-T cells therapy for preventing
AKI [72]. In patients who develop severe CRS, admission
in critical care units for supportive treatment is justified.
Moreover, interleukin-6 receptor blockers, such as toci­
lizumab, are useful to reduce systemic inflammation and,
consequently, are useful in preventing the development
and in the management of AKI related to CAR-T cells
therapies [71].
Immune Checkpoint Inhibitors (CTLA-4 Inhibitors,
PD-1 Inhibitors, PD-L1 Inhibitors)
Immune checkpoint inhibitors (CPI) have revolution-
ized the treatment of some malignancies, and their use is
increasing day by day [73, 74] because of its striking effect
on improving survival rates [75, 76]. CPI enhance tumor-
directed immune responses by binding inhibitory recep-
tors such as cytotoxic T-lymphocyte-associated protein 4,
and the programmed death protein 1 or its ligand on T
cells and other immune cells causing a downregulation of
its activation. CPI binds to cytotoxic T-lymphocyte-asso-
ciated protein 4, programmed death protein 1 or its li-
gand to activate immune cells from a quiescent state –
triggering a vigorous response against tumor cells [77].
Since CPI mechanisms are not selective, these drugs cause
diverse autoimmune phenomena known as immune-re-
lated adverse events. AKI incidence in patients under CPI
treatment has been increasing to 13–29% as long as CPI
use has become more ordinary, however biopsy-proven
or clinically CPI-related AKI has been only found in 2%–
3% [78, 79]. In patients under CPI treatment, the develop-
ment of AKI has been identified as a risk factor for mor-
tality [80] as well as an absence of renal recovery after an
AKI episode [78]. Risk factors for AKI related to CPI are
Anticancer Drug-Related Nephrotoxicity
patient age, impaired baseline renal function, concomi-
tant use of proton pomp inhibitors, a combination of
more than one CPI and the presence of previous im-
mune-related adverse events [78–81]. A special charac-
teristic of AKI-related to CPI is that it occurs from some
weeks to many months after treatment initiation [82].
The most frequent renal histologic pattern in patients
with biopsy-proven CPI-related AKI is acute tubuloint-
erstitial nephritis (ATIN) [83] but glomerular lesions
have also been described, such as renal vasculitis, podo-
cytopathies, and C3 glomerulonephritis [84]. When com-
pared to classical ATIN, CPI-related ATIN presented
with lower creatinine at diagnosis, higher urinary leuco-
cyte counts, and time from initiation of the culprit drug
to ATIN diagnosis was longer in patients with CPI-relat-
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ed ATIN than in those with classical ATIN [85]. Recom-
mendations for kidney biopsy in patients with CPI-relat-
ed AKI are becoming more limited as long as experience
in treating this entity has grown. Currently, a biopsy is
recommended for AKI stages 2 and 3 and when a clinical
suspicion of glomerular injury exists (i.e., nephrotic range
proteinuria, oliguria, dysmorphic hematuria) [4]. CPI
withdrawal is mandatory in CPI-related AKI and cortico-
steroids therapy should be initiated if ATIN is clinically
suspected [78, 86].
Other Therapies
Bisphosphonates
Bisphosphonates have the ability to inhibit osteoclast-
mediated bone destruction, so they are used as the treat-
ment of malignant bone diseases. Furthermore, they have
been shown antitumor activity by acting together with
other antineoplastic drugs [87]. In contrast to oral
bisphosphonates, that are used mainly to treat postmeno-
pausal osteoporosis, intravenous bisphosphonates such
as zoledronate and pamidronate are related to potential
nephrotoxicity that limits its use. Kidney damage is re-
lated to dose and infusion time and both pamidronate
and zoledronate could cause acute tubular necrosis and
nephrotic syndrome with FSGS histologic pattern. For
that reason, renal function should be monitored prior to
treatment infusion and, if SCr rises, the drug should be
discontinued. In addition, renal damage could be pre-
vented by increasing the time interval between doses and
by strict adherence to guidelines dose recommendations
adjustment by baseline renal function. Ibandronate has
not been related to renal damage even in patients with
CKD [4, 88].
Nephron 2023;147:65–77 73
DOI: 10.1159/000525029
 mTOR Inhibitors
Everolimus is approved for the treatment of breast
cancer, neuroendocrine tumors (pancreas, lung, or gas-
trointestinal), advanced renal-cell carcinoma, angiomyo-
lipoma in tuberous sclerosis complex, astrocytoma, and
other types of malignancies, as well as sirolimus, a related
agent [89]. The main renal complication of everolimus
and sirolimus is proteinuria, reported in 3%–36% of pa-
tients. Sirolimus has also been associated with nephrotic
syndrome in 2% of cases, with an FSGS and membrano-
proliferative histologic pattern. mTOR inhibitor-related
proteinuria mechanism is not well known but it could be
in part related to a decreased production of VEGF in
podocytes or to a decreased expression of cubilin and
megalin that leads to a decreased tubular albumin reup-
take. If proteinuria is mild to moderate, ACE inhibitors
or ARB and lifestyle modifications are recommended,
and mTOR inhibitor withdrawal is not necessary. In con-
trast, in patients with severe proteinuria or nephrotic syn-
drome, discontinuation of the culprit drug may be the
strategy to prevent AKI. Plasmapheresis could be benefi-
cial in patients with focal and segmental glomeruloscle-
rosis or membranoproliferative glomerulonephritis [4,
49].
Calcineurin Inhibitors
Calcineurin inhibitors (CNIs), both tacrolimus and
cyclosporine A, are drugs that are well known by nephrol-
ogists because they are part of the classical immunosup-
pressive regimen in renal transplantation, as well as in
other solid organ transplantation. However, CNI are also
used in allogenic hematopoietic stem-cell transplantation
(HSCT) and, as happens in renal transplantation, their
use may be associated with AKI. Major renal effects of
CNI are renal vessel constriction, endothelial damage,
and tubular toxicity. However, cyclosporine A and tacro-
limus can also cause CNI-related TMA [4], that some-
times is limited to kidney but can also have peripheral
expression that sometimes requires supportive care in re-
cent HSCT recipients. CNI are also used as immunosup-
pressive treatment of aplastic anemia in ineligible pa-
tients for first-line therapy, HSCT [90].
Conclusions
Cancer treatment including conventional chemother-
apy, targeted cancer agents, and immunotherapies among
others are significantly associated with kidney injury in
terms of acute and CKD. The new therapies alone or in
74 Nephron 2023;147:65–77
DOI: 10.1159/000525029
combination with the classical ones have nicely demon-
strated to increase the life expectancy of the patients with
advanced malignancy; however, they have been highly as-
sociated with renal toxicity that worsens the patient qual-
ity of life and increases mortality. As there is a bidirec-
tional axis between cancer and kidney injury, the con-
solidation of dedicated onconephrology clinics is crucial
at least in referral hospitals.
Conflict of Interest Statement
M.J. Soler reports honorarium for conferences, consulting fees,
and advisory boards from Astra Zeneca, Novo Nordsik, Esteve,
Vifor, Bayer, Mundipharma, Ingelheim Lilly, Jansen, ICU Medi-
cal, Travere Therapeutics, and Boehringer. C.G.-C. has received
Downloaded from http://karger.com/nef/article-pdf/147/2/65/3915619/000525029.pdf by guest on 22 June 2023
travel and congress fees support from AstraZeneca, Esteve, Novo-
Nordisk, Boehringer Ingelheim Lilly, Astellas, Otsuka, Novartis,
Astellas, and Baxter and has given scientific lectures and partici-
pated in advisory boards organized by AstraZeneca, Boehringer
Ingelheim Lilly, Mundipharma, and NovoNordisk.
Funding Sources
This work was supported by grants from Fondo de Investig-
ación Sanitaria-FEDER, ISCIII, Río Hortega CM20/00111,
PI17/00257, EIN2020-1123381, RD16/0009/0030 (REDINREN),
and RD21/0005/0016 (RICORS 2040).
Author Contributions
Conceptualization; writing – revision draft preparation, re-
view, and editing; and supervision: Juliana Draibe, Clara García-
Carro, and María José Soler. All authors have read and agreed to
the published version of the manuscript.
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