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Background:
Systematic Review

Nephrotoxicity of Immune Checkpoint Inhibitors in Single and Combination Therapy—A Systematic and Critical Review

by
Javier Tascón
1,2,3,4,
Alfredo G. Casanova
1,2,3,4,
Laura Vicente-Vicente
1,2,3,4,
Francisco J. López-Hernández
2,3,4,5 and
Ana I. Morales
1,2,3,4,5,*
1
Toxicology Unit, Universidad de Salamanca (USAL), 37007 Salamanca, Spain
2
Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain
3
Department of Physiology and Pharmacology, Universidad de Salamanca (USAL), 37007 Salamanca, Spain
4
Group of Translational Research on Renal and Cardiovascular Diseases (TRECARD), 37007 Salamanca, Spain
5
Group of Biomedical Research on Critical Care (BioCritic), 47005 Valladolid, Spain
*
Author to whom correspondence should be addressed.
Biomedicines 2025, 13(3), 711; https://doi.org/10.3390/biomedicines13030711
Submission received: 8 January 2025 / Revised: 5 March 2025 / Accepted: 10 March 2025 / Published: 13 March 2025
(This article belongs to the Special Issue The Development of Cancer Immunotherapy)
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Abstract

:
Background/Objectives: Immune checkpoint inhibitors (ICIs) have generated a revolutionary approach in the treatment of cancer, but their effectiveness has been compromised by immune-related adverse events, including renal damage. Although rare, these effects are relevant because they have been related to poor patient prognoses. The objective of this review was to estimate the current incidence of nephrotoxicity in patients treated with single and double ICI therapies. Methods: A total of 1283 potential articles were identified, which were reduced to 50 after applying the exclusion and inclusion criteria. Results: This study reveals the increase in acute kidney injury associated with these drugs in the last decade and shows that, interestingly, combined therapies with ICIs does not lead to an increase in kidney damage compared with anti-CTLA-4. It also suggests that kidney damage could be underdiagnosed when it comes to interstitial nephritis, because definitive evidence requires a renal biopsy. Conclusions: In perspective, these conclusions could guide clinicians in making decisions for therapy personalization and highlight the need to search for new diagnostic systems that are more sensitive and specific to the type of damage and could replace the biopsy.

1. Introduction

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies specifically directed at blocking immune checkpoints (molecules that regulate the balance between the elimination of foreign antigens and the recognition of autoantigens). These are IgG1-, IgG2-, and IgG4-type human or humanized immunoglobulins. Their pharmacological activity lies in blocking the inhibitory receptors found on T cells, thus allowing their activation and increasing the immune response. Consequently, ICIs reestablish the action of T cells against tumors [1,2].
ICIs have changed the treatment paradigm for several types of tumors with poor prognoses in the last decade. There are three ICI families available for clinical use. On the one hand are those that block immune checkpoints or inhibitory T-cell receptors, i.e., antibodies binding to and blocking the cytotoxic T lymphocyte-associated protein 4 (CTLA-4), representing the anti-CTLA-4 family, and those that prevent the binding of activating ligands to the programmed cell death protein 1 (PD-1), constituting the anti-PD-1 family. On the other hand, there is another family of antibodies that bind to and block the ligands found on tumor cells (PD-L1), which bind and activate PD-1 receptors in lymphocytes. These form the anti-PD-L1 antibody family [1,2].
In 2011, the United States Food and Drug Administration (FDA) approved the first ICI with a therapeutic indication to treat metastatic melanoma cancer. This anti-CTLA-4 antibody, named ipilimumab, was the pioneer preceding eight currently authorized antibodies: tremelimumab (anti-CTLA-4); nivolumab, pembrolizumab, cemiplimab, and dostarlimab (anti-PD-1); and avelumab, durvalumab, and atezolizumab (anti-PD-L1) [3,4].
The clinical use of these nine FDA-approved ICIs has expanded over more than nineteen different therapeutic indications [5]. Furthermore, combined ICI therapy poses a breakthrough in the treatment of some types of cancer, such as non-small-cell lung cancer and metastatic melanoma, in which the concomitant administration of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) increases the response rate and survival [6].
However, despite their innovative nature and the improvement in efficacy and safety, the use of these drugs has also unveiled a number of adverse events related to the immune system resulting from the boost in the immune response [7]. The incidence of adverse effects appears to be higher in patients receiving combined therapy compared with those receiving monotherapies, which would limit their use [8].
Kidney injury is one of the complications observed. Although not the commonest, renal toxicity is a relevant complication associated with a poorer prognosis [5]. Acute kidney injury (AKI), proteinuria, and electrolyte disorders are the main pathologies of the renal system associated with ICI treatment [9], and the most common pathological lesion that leads to AKI is tubulointerstitial nephritis (90% of cases) [10]. There are also other lesions associated with the autoreactivity of the immune system, such as glomerulonephritis [11].
Since the introduction of these drugs in 2011, the incidence of undesired renal effects has grown due to the increasing use and abundance of authorized ICIs and improved diagnosis [12]. Systematic reviews and meta-analyses dealing with the incidence of renal damage in patients treated with immune checkpoint inhibitors have been previously published, such as those by Liu et al. 2023 [13] and Xie et al. 2023 [14]. However, due to the limited experience accumulated since the recent introduction of these drugs, updated knowledge on incidence, based on the progressively increasing data available, may help guide decision making and optimize treatment. On these grounds, we aimed to estimate the current incidence of nephrotoxicity in cancer patients treated with single and double ICI therapies.

2. Materials and Methods

2.1. Retrieval of Published Studies

A bibliographic search of clinical studies published in Medline and the Web of Science databases until 4 September 2024 was carried out by entering the following keyword combinations: “(nephrotoxicity OR renal toxicity OR renal damage OR renal injury OR kidney injury OR kidney damage) AND (immune checkpoint inhibitor OR ICI OR ICPI OR ipilimumab OR tremelimumab OR nivolumab OR pembrolizumab OR cemiplimab OR atezolizumab OR durvalumab OR avelumab OR PD-1 OR CTLA-4 OR PD-L1)”. The filters used were: “Humans”, “English”.

2.2. Exclusion and Inclusion Criteria

Study selection was carried out following the PRISMA guidelines. Two researchers (J.T. and L.V.-V.) independently withdrew those articles that met any of the following exclusion criteria: (1) preclinical studies, (2) reviews, protocols, communications, and letters to the editor, (3) written in a language other than English, (4) full text not available, and (5) studies evaluating the renal safety of combined therapies of ICIs with other antineoplastic drugs. After that, they selected those studies that met all of the following inclusion criteria: (1) clinical studies evaluating at least one ICI drug and (2) evaluating at least one kidney damage parameter: AKI or nephritis (independently for each ICI family). Discrepancies in article selection were resolved by a third researcher (A.G.C.). The screening was carried out with the online tool “Systematic review facility” [15].
This protocol was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY registration number: INPLASY202510053) [16].

2.3. Data Extraction

The following data were extracted from each included work: first author’s name, publication year, study design and duration, geographic location, number of patients included, patient characteristics, tumor type and stage, ICI drugs, posology, route of administration, duration of treatment, Jadad or MINORS scale, and number of patients who presented alterations in any of the following parameters of kidney damage: AKI (elevation of plasma creatinine or renal failure) and nephritis. Study quality was assessed with the Jadad scale [17] (for prospective randomized studies) or the MINORS scale [18] (for retrospective or prospective, non-randomized studies). A threshold score of 2 out of 5 (in the Jadad scale) or 7 out of 16 (in the MINORS scale) was established for inclusion in this review.

2.4. Calculation of Incidence

In each clinical study, percentage incidence of AKI and nephritis were calculated according to the following formula:
I n c i d e n c e   % = N u m b e r   o f   c a s e s   ( A K I   o r   n e p h r i t i s ) T o t a l   n u m b e r   o f   p a t i e n t s × 100
The weighted mean and the standard error of the mean of AKI and nephritis incidence in ICI families and in the anti-PD-1 + anti-CTLA-4 combination were also calculated. In addition, the weighted mean and the standard error of the mean of the incidence of the kidney damage parameters of nivolumab (anti-PD-1), pembrolizumab (anti-PD-1), atezolizumab (anti-PD-L1), durvalumab (anti-PD-L1), ipilimumab (anti-CTLA-4), tremelimumab (anti-CTLA-4), nivolumab + ipilimumab (anti-PD-1 + anti-CTLA-4), and pembrolizumab + ipilimumab (anti-PD-1 + anti-CTLA-4) were also calculated. Figures design was carried out with Microsoft Office 365® software (Redmond, WA, USA).

3. Results

The flow chart describing the study search process and definitive inclusion of cited references is presented in Figure 1. A total of 1283 potential articles were identified, which, after applying the exclusion and inclusion criteria, was reduced to 44 selected articles. During the data extraction stage of the studies, 6 new articles were included from related searches, adding up to a total of 50 clinical studies. The descriptive data of the 50 clinical studies finally included in the review are shown in Table 1.
The 50 clinical studies analyzed in this review were mostly retrospective studies and a few prospective and randomized clinical trials carried out in different hospitals worldwide, mostly with metastatic melanoma and metastatic renal cancer patients, but also with patients with other types of cancer such as non-small-cell lung cancer. The most commonly used ICIs were nivolumab and pembrolizumab (anti-PD-1), ipilimumab (anti-CTLA-4), and the combined therapy of nivolumab + ipilimumab. These drugs were administered intravenously for several cycles, essentially every 2 or 3 weeks. The most frequently quantified parameter to evaluate renal function was the elevation of plasma creatinine.
The incidence of AKI was practically similar in the groups of anti-PD-1 (5.32%) and anti-PD-L1 (5.25%) but increased in patients treated with anti-CTLA-4 drugs (7.83%). Yet, it is noteworthy that ipilimumab had a higher incidence of AKI than tremelimumab (7.87% versus 4.35%, respectively). The higher incidence of AKI observed with ipilimumab may be related to the longer period of time that this drug has been used in clinical practice and the greater number of observational studies available (ipilimumab was the first ICI approved by the FDA in 2011, in contrast to tremelimumab, which was approved in 2022) [4]. On the other hand, the incidence of AKI in the combined therapy group (anti-PD-1 + anti-CTLA-4) was 5.58% (Table 2).
The mean incidence of nephritis in patients treated with anti-PD-1 did not exceed 1.5% (Table 2). However, the clinical study carried out by O’Reilly et al. in 2019 reported an incidence of nephritis of 3.39% in patients treated with ipilimumab [45]. In relation to the combined drug therapy (anti-PD-1 + anti-CTLA-4), the mean incidence of nephritis reached values around 2%, although the study carried out by Tykody et al. in 2022 evidenced an incidence of nephritis in patients treated with nivolumab + ipilimumab of 3.85% [62].

4. Discussion

ICIs have revolutionized the treatment of certain types of tumors, but their effectiveness has been limited by adverse effects related to the immune system, including renal effects [9,68]. Furthermore, numerous clinical studies have validated their advantageous efficacy profile not only when administered as monotherapy or in combination, but also when combined with chemotherapy, which has led to an increase in the survival of cancer patients [69].
Our study reveals that the incidence of AKI has kept growing in recent years (anti-PD-1 ~5%, anti-PD-L1 ~5%, anti-CTLA-4 ~8%, anti-PD-1 + anti-CTLA-4 ~6%), leaving outdated the previous incidence values of 2–3% for monotherapies and 5% for combined therapies [70]. The actual incidence of nephrotoxicity might be even higher, and damage is likely underdiagnosed in subclinical, asymptomatic, and mild cases due to the poor and sub-optimally sensitive diagnosis technology. In fact, current diagnosis of AKI is curtailed by the known limitations in sensitivity and specificity of the standard biomarker, plasma creatinine [71].
According to the existing literature, nephritis is the cause of 90% of ICI nephrotoxicity cases [10]. However, in this study we did not find incidences of nephritis that were too high (between 1 and 3%) for what would be expected taking into account that nephritis is the main cause of nephrotoxicity. This suggests that nephritis could be underestimated in many studies because definitive diagnosis is made by biopsy [70], which is medically restricted because of its invasive nature and potential complications [72].
ICIs’ toxicity is related to their pharmacological action, namely the release of the physiological blockages that regulate the immune response [9,68]. However, the anti-CTLA-4 and anti-PD-1/anti-PD-L1 families act differently because they differ in the location of their molecular targets, the stage of T-cell activation they facilitate, and the signaling pathways involved [73]. This could be the reason why the anti-PD-1 family is more effective and less toxic than the anti-CTLA-4 family, a fact that has been observed in various types of cancer, such as advanced melanoma [74,75,76]. This systematic review agrees with previous studies that show a higher incidence of adverse effects (also AKI) in patients treated with anti-CTLA-4 drugs compared with those treated with anti-PD-1.
The joint administration of anti-PD-1/anti-PD-L1 and anti-CTLA-4 could provide synergistic efficacy due to the combination of their different mechanisms of action, which could justify a higher response rate and survival of patients. However, this increase in efficacy could also entail an upsurge in adverse effects [6] that limit their use. With regard to nephrotoxicity, our study contrasts with the existing literature [6,77]. The incidence of AKI following the single anti-CTLA-4 treatment is 7.83%, while after combined therapy of anti-PD-1 + anti-CTLA-4, it is not greater (5.58%). These data suggest that the combined therapy would provide a benefit from an improved antitumor efficacy with no additional nephrotoxic burden.
The findings highlighted in this review updating the kidney damage incidence data reveal the favorable benefit–risk balance of combined ICI therapies in order to improve clinical decision making [23,24,35,63]. In many cases, this could be a successful therapeutic strategy, which would allow two families of ICIs to be included in the therapy without increasing the risk of suffering adverse renal effects (the incidence of kidney damage is not greater than after a single anti-CTLA-4). This is an important piece of information for clinical decision making, since recent systematic reviews, such as that by Xie et al., 2023 [14], report higher incidences of renal damage for combined ICI therapy than for monotherapies.
The different toxicities of these drug families could be related to the mechanism of action of each of them. The blockade carried out by anti-CTLA-4 on the CTLA-4 receptor at the lymph node level alters the quiescence phase of T cells and promotes their activation. This blockade of the inhibitory receptor restores the activating signal of the CD28 costimulatory receptor. Consequently, T cells are activated, and the adaptive immune response against tumor cells is regenerated [9,78]. However, PD-1/PD-L1 blockade occurs at a different site than CTLA-4 blockade. It affects the effector phase of the adaptive immune response and takes place in the tumor microenvironment [68]. In this sense, the T cell–CD28 costimulatory receptor signaling pathway is reestablished. As a result, the production of cytokines, the proliferation of T lymphocytes, and the cytotoxic activity of the T cell is promoted [9,73,78]. This would translate, in addition to the therapeutic response, into the appearance of adverse effects, including kidney effects, due to the attack of autoantigens as a consequence of the overactivation of the lymphocyte system.
Regarding the signaling pathways affected in T lymphocytes (Figure 2), the inhibitory signals through PD-1 and CTLA-4 converge on serine-threonine kinase (AKT), although the inhibition pathways are different. Parry RV et al. demonstrated that PD-1 signaling blocks CD28-mediated activation of inositolphosphatidyl-3-kinase (PI3K) and AKT. Inhibitory CTLA-4 signaling preserves PI3K activity but inhibits AKT directly through the activation of the phosphatase protein PP2A. Therefore, anti-CTLA-4 and anti-PD-1 antibodies would act at different levels in the T-cell signaling cascade in order to stimulate immune activation [78].
Recently, anti-CTLA-4 drugs have been called “immune enhancers”, and anti-PD-1/anti-PD-L1 drugs “immune normalizers” [79]. In this sense, anti-PD-1/anti-PD-L1 would cause a normalization of immunity, while anti-CTLA-4 would enhance it. This fact could justify the greater renal toxicity produced by anti-CTLA-4 drugs with respect to anti-PD-1/anti-PD-L1.
Several hypotheses have been proposed to explain the nephrotoxicity of ICIs (Figure 3). One of these is the reactivation of specific T cells (in the latency period) that had been generated after the administration of other nephrotoxic drugs (proton pump inhibitors, non-steroidal anti-inflammatory drugs, and antibiotics) [80] and which could now attack renal autoantigens. Alternatively, ICIs could cause an abnormal proliferation and activation of autoreactive T-cell clones or the production of autoantibodies by B cells recognizing self-antigens in tubular epithelial cells, mesangial cells, or podocytes, until then tolerated by the immune system [9]. A third potential mechanism would be the inflammatory environment generated within kidney tissue by proinflammatory cytokines secreted by T cells. Finally, because renal tubular cells constitutively express PD-L1 to avoid T cell-mediated autoimmunity, blocking its interaction with PD-1 in T cells could disable the defense and facilitate cytotoxic injury [81].
Our study has encountered a few caveats that limit coherent comparison among the studies, which need to be addressed in future studies reporting ICI nephrotoxicity. For instance, the absence of a standard definition and diagnostic criteria for ICI nephropathy prevents the full leverage and integration of data from multiple studies. An international consensus initiative is necessary in this regard.
In conclusion, this review reveals an increased incidence of AKI associated with ICI drugs that should alert clinicians, especially in patients at risk. On the other hand, it also shows that combined ICI therapy is not more nephrotoxic than single anti-CTLA-4 therapy, underpinning a better efficacy-to-safety relation than previously reported. Finally, it suggests that kidney damage could be underdiagnosed because of the absence of reliable, non-invasive technology for differential diagnosis, as conclusive diagnosis still requires a biopsy.
There is a need to search for new, earlier, and more sensitive diagnostic systems. In this sense, new, preferably urinary, biomarkers or, more probably, collections of biomarkers are sought to compose etiological fingerprints with which to differentiate underlying damage patterns through a liquid biopsy. In addition, longer term follow-up studies should be conducted to monitor the evolution and duration of renal side effects and the sequelae of single and double therapies with traditional and new diagnostic methods under a unified definition of ICI nephropathy that allows for cross-study data standardization and comparison.

Author Contributions

Conceptualization, A.I.M.; methodology, J.T., A.G.C. and L.V.-V.; investigation, J.T.; data curation, A.I.M.; writing—original draft preparation, J.T.; writing—review and editing, A.I.M., A.G.C., L.V.-V. and F.J.L.-H.; supervision, A.I.M. and F.J.L.-H. All authors have read and agreed to the published version of the manuscript.

Funding

This study was funded by the Instituto de Salud Carlos III (ISCIII) through the project “PI20/01351”, co-funded by the European Union; and RICORS2040 (Kidney Disease) of the Instituto de Salud Carlos III (RD21/0005/0004 and RD24/0004/0024), co-funded by the European Union—NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). Javier Tascón is a recipient of a predoctoral fellowship from the University of Salamanca, co-funded by Banco Santander.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviation

AKIAcute kidney injury
AKTSerine-threonine kinase
CTLA-4Cytotoxic T lymphocyte-associated protein 4
FDAUnited States Food and Drug Administration
ICIsImmune checkpoint inhibitors
IgG1G1 immunoglobulin
IgG2G2 immunoglobulin
IgG4G4 immunoglobulin
PD-1Programmed cell death protein 1
PD-L1Ligand 1 of programmed cell death protein
PI3KInositolphosphatidyl-3-kinase
PP2APhosphatase protein 2A

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Figure 1. Flow chart of search and selection of studies carried out in accordance with the PRISMA guidelines.
Figure 1. Flow chart of search and selection of studies carried out in accordance with the PRISMA guidelines.
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Figure 2. Signaling pathways affected in T lymphocytes due to the inhibition of check points. Blue arrows mean activation, and red lines mean inhibition.
Figure 2. Signaling pathways affected in T lymphocytes due to the inhibition of check points. Blue arrows mean activation, and red lines mean inhibition.
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Figure 3. Mechanisms of kidney damage associated with immune checkpoint inhibitors.
Figure 3. Mechanisms of kidney damage associated with immune checkpoint inhibitors.
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Table 1. Descriptive characteristics of the studies included in the systematic review. Acute kidney injury (AKI).
Table 1. Descriptive characteristics of the studies included in the systematic review. Acute kidney injury (AKI).
Study IdentificationDesignLocationDuration of RecruitmentTumor Type and StageNumber of Patients Initially IncludedPatient CharacteristicsDrugPosologyParameters of Renal InjuryJadad/MINORS Scale
AKINephritis
Abdelrahim et al., 2021 [19]Retrospective studyUSA1 January 2010 to 12 November 2019Metastatic or advanced melanoma 1664Black, Hispanic, Asian, and White ethnicity. Median age 63 years.Nivolumab,
pembrolizumab,
atezolizumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab + ipilimumab		Not specifiedYesNo10 of 16 (MINORS)
Antonia et al., 2016 [20]Multicenter, open-label, two-stage, multi-arm phase 1/2 trialFinland, Germany, Italy, Spain, UK, and USA18 November 2013 to 28 July 2015Extensive stage non-small-cell lung cancer216White, Black or African American, and other ethnicities. Median age 63 years.Nivolumab, nivolumab + ipilimumab3 mg/kg every 2 weeks
1 mg/kg + 1 mg/kg. Depending on tolerability, 1 mg/kg + 3 mg/kg or 3 mg/kg + 1 mg/kg every 3 weeks		YesNo12 of 16 (MINORS)
Apolo et al., 2020 [21]Phase 1, open-label, multicohort trialUSA3 September 2014 to 15 March 2016Advanced or metastatic urothelial cancer249Ethnicity not specified. Median age 69 years.Avelumab10 mg/kg every 2 weeksYesNo10 of 16 (MINORS)
Atkins et al., 2018 [22]Open-label, multicohort, phase 1b studyUSA2 April 2014 to 18 November 2014Advanced melanoma and advanced renal cell carcinoma39Ethnicity not specified. Median age 60.5 years.Pembrolizumab + ipilimumab2 mg/kg + 1 mg/kg every 3 weeksYesNo3 of 5 (Jadad)
Atkins et al.
2023
[23]		Single-arm, open-label, non-randomized, multicenter, phase 2 studyUSAMay 2017 to December 2019Metastatic renal cancer35Ethnicity not specified. Median age 65 years.Nivolumab
nivolumab + ipilimumab		240 mg every 2 weeks
3 mg/kg and 1 mg/kg i.v. every 12 weeks		YesNo11 of 16 (MINORS)
Blas et al.
2024
[24]		Retrospective studyUSA2013 to 2022Metastatic renal cancer2921Ethnicity not specified. Median age 65 years.Nivolumab + ipilimumabNot specifiedYesYes10 of 16 (MINORS)
Campbell et al., 2021 [25]Pilot studyUSA7 November 2016 to 25 October 2018Metastatic renal cancer30Hispanic or Latino and White or Caucasian ethnicity. Median age 64 years. Tremelimumab10 mg/kg every 4 weeksYesNo2 of 5 (Jadad)
Cortazar et al., 2020 [11]Multicenter, retrospective cohort studyUSA and CanadaNot specifiedMelanoma, lung, genitourinary, others414White, Black, and Asian ethnicity. Median age 67 years.Nivolumab, pembrolizumab, ipilimumabNot specifiedYesNo9 of 16 (MINORS)
Dizman et al., 2022 [26]Single-center, open-label, investigator-initiated trialUSA22 April 2019 to 30 December 2020Metastatic renal cancer30White and Asian ethnicity. Median age 64 years.Nivolumab + ipilimumab3 mg/kg + 1 mg/kg every 3 weeks followed by nivolumab monotherapy at 480 mg monthlyYesNo3 of 5 (Jadad)
Espi et al.,
2021 [27]		Retrospective analysisFranceJanuary 2015 to July 2017Advanced melanoma, non-small-cell lung cancer, and urologic cancers352Ethnicity not specified. Median age 67 years.Nivolumab, pembrolizumabNot specifiedYesNo10 of 16 (MINORS)
Flippot et al., 2019 [28]Phase 2 trialFrance12 February 2016 to 27 July 2017Brain metastases from renal cell carcinoma73Ethnicity not specified. Median age 59.5 years.Nivolumab3 mg/kg every 2 weeksYesNo11 of 16 (MINORS)
George et al., 2022 [29]Largely community-based, multicohort, open-label, phase 3b/4 trialUSAJanuary 2017 to March 2018Advanced renal cell carcinoma106White, Black or African American, and other ethnicities.
Median age 64.5 years.		Nivolumab + ipilimumab6 mg/kg + 1 mg/kg every 8 weeksYesYes13 of 16 (MINORS)
Goldberg et al., 2020 [30]Two-arm phase 2 trialUSA31 March 2014 to 21 May 2018Brain metastases from stage IV non-small cell lung cancer42Ethnicity not specified. Median age 60 yearsPembrolizumab10 mg/kg every 2 weeksYesNo10 of 16 (MINORS)
Grimm et al., 2022 [31]Prospective, observational, multicenter studyGermanyOctober 2016 to December 2018Advanced renal cell carcinoma228Ethnicity not specified. Median age 70 yearsNivolumab3 mg/kg every 2 weeks, 240 mg every 2 weeks, or 480 mg every 4 weeksYesNo11 of 16 (MINORS)
Gul et al.,
2020 [32]		Retrospective studyUSANot specifiedMetastatic renal cell carcinoma45Ethnicity not specified. Median age 62 yearsNivolumab + ipilimumabNot specifiedNoYes10 of 16 (MINORS)
Hammers et al., 2017 [33]Multicenter, open-label, phase 1 studyNot specifiedFebruary 2012 to May 2014Metastatic renal cell carcinoma194White, Asian, Black or African American, and other ethnicities. Median age 55 years.Nivolumab + ipilimumab3 mg/kg + 1 mg/kg, 1 mg/kg + 3 mg/kg, or 3 mg/kg + 3 mg/kg every 3 weeks YesNo2 of 5 (Jadad)
Hofmann et al., 2016 [34]Retrospective studyGermany and SwitzerlandNot specifiedMetastatic melanoma496Ethnicity not specified. Median age 59 years.Nivolumab, pembrolizumab3 mg/kg every 2 weeks
2 mg/kg every 3 weeks		NoYes9 of 16 (MINORS)
Izumi et al.
2023
[35]		Retrospective studyJapanSeptember 2018 to February 2021Metastatic renal cell carcinoma131Ethnicity not specified. Median age 65 years.Nivolumab + ipilimumab240 mg and 1 mg/kg i.v every 3 weeks YesNo10 of 16 (MINORS)
Julien et al., 2020 [36]Phase 1/2, open-label studyUSA, Spain, Hong Kong, and SingaporeUntil March 2017Advanced hepatocellular carcinoma262Ethnicity not specified. Median age 63 years.Nivolumab0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, or 10.0 mg/kg every 2 weeksYesYes11 of 16 (MINORS)
Kanz et al.,
2016 [37]		Multicenter, retrospective studyGuyana6 January 2013 to 31 December 2015Advanced renal cell carcinoma,
melanoma, non-small-cell lung cancer, small-cell lung cancer, and urothelial bladder cancer		27Ethnicity not specified. Median age 69 years.Nivolumab, pembrolizumabNot specifiedNoYes9 of 16 (MINORS)
Martini et al., 2018 [38]Retrospective cohort studyUSA, Spain, BrazilNot specifiedMetastatic renal cell carcinoma19Ethnicity not specified. Median age 63 years.Anti-PD-1
Anti-PD-L1		Not specifiedNoYes7 of 16 (MINORS)
Massard et al., 2016 [39]Phase 1/2 multicenter, open-label studyNot specified28 August 2014 to 10 November 2015Advanced urothelial
bladder cancer		61White, Asian, Black or African American, and other ethnicities. Median age 66 years.Durvalumab10 mg/kg every 2 weeksYesNo11 of 16 (MINORS)
McFarlane et al., 2020 [40]Open-label, phase 3b/4 studyUSADecember 2015 to December 2016Advanced clear-cell renal cell carcinoma97Ethnicity not specified. Median age 64.7 years.Nivolumab240 mg every 2 weeksNoYes10 of 16 (MINORS)
Meraz-Muñoz et al.,
2020 [41]		Retrospective cohort studyCanada1 January 2010 to 1 January 2017Metastatic melanoma, lung, genitourinary, lymphoma, ovarian, and colon cancer309Ethnicity not specified. Median age 63 years.Nivolumab, pembrolizumab,
ipilimumab,
nivolumab + ipilimumab		Not specifiedYesNo9 of 16 (MINORS)
Mok et al.,
2019 [42]		Randomized, open-label, controlled, phase 3 trialArgentina, Brazil, Bulgaria, Canada, Chile, China and Hong Kong Special Administrative Region, Colombia, Czech Republic, Estonia, Guatemala, Hungary,
Japan, Latvia, Lithuania, Malaysia, Mexico, Peru,
Philippines, Poland, Portugal, Romania, Russia, South
Africa, South Korea, Sweden, Switzerland, Taiwan,
Thailand, Turkey, Ukraine, and Vietnam		19 December 2014 to 6 March 2017Locally advanced or metastatic
non-small-cell lung cancer		1275Ethnicity not specified. Median age 63 years.Pembrolizumab200 mg every 3 weeksYesNo3 of 5 (Jadad)
Mourey et al.
2024
[43]		Phase 2 studyFranceNot specifiedMetastatic renal cancer720Ethnicity not specified. Median age 70 years.Nivolumab3 mg/kg every 2 weeksYes No8 of 16 (MINORS)
Noronha et al., 2021 [44]Single-center retrospective analysisIndiaAugust 2015 to November 2018Advanced head and neck cancer, lung cancer, adenocarcinoma, squamous cell carcinoma, small-cell lung cancer, renal cell carcinoma, urothelial carcinoma, malignant mesothelioma (advanced non-melanoma solid tumors)155Ethnicity not specified. Median age 57 years.Nivolumab, pembrolizumab3 mg/kg every 2 weeks/240 mg flat dose every 2 weeks
200 mg flat dose every 3 weeks		NoYes9 of 16 (MINORS)
O’Reilly et al., 2020 [45]Retrospective studyUnited KingdomMay 2017 to August 2017Metastatic melanoma84Ethnicity not specified. Median age 65 years.Nivolumab, pembrolizumab,
ipilimumab		Not specifiedNoYes10 of 16 (MINORS)
Polkowska et al., 2019 [46]Retrospective observational studyPolandMarch 2013 to October 2016Metastatic melanoma1170Ethnicity not specified. Median age 61 years.IpilimumabNot specifiedYesNo10 of 16 (MINORS)
Powles et al., 2020 [47]Open-label, randomized, controlled, phase 3 trialChina24 November 2015 to 21 March 2017Locally advanced or metastatic urothelial carcinoma1032White or Caucasian, Asian, Black or African American, and other ethnicities. Median age 67.5 years.Durvalumab, durvalumab + tremelimumab1500 mg every 4 weeks 1500 mg + 75 mg every 4 weeksYesNo3 of 5 (Jadad)
Powles et al., 2022 [48]Multicenter, randomized, double blind, placebo-controlled, phase 3 trialNorth America, South America, Europe, Asia, and Australia30 June 2017 to 20 September 2019Advanced clear-cell renal cell carcinoma994Hispanic or Latino and not Hispanic ethnicity. Median age 60 years.Pembrolizumab200 mg every 3 weeksYesYes5 of 5 (Jadad)
Raghav et al., 2022 [49]Phase 2 study, open-label, single-center, multicohort trial.USA29 August 2016 to 29 June 2020Advanced solid tumors29Ethnicity not specified. Median age 59 years.Pembrolizumab200 mg every 3 weeksYesNo10 of 16 (MINORS)
Rassy et al., 2022 [50]Retrospective analysisFranceFebruary 2016 to July 2017Advanced renal cell carcinoma729Ethnicity not specified. Median age 64 years.Nivolumab3 mg/kg every 2 weeksYesNo10 of 16 (MINORS)
Ready et al., 2023 [51]Phase 3B, multicenter, open-label, single-arm, multicohort safety studyNorth America, Europe, and South AmericaNovember 2016 to 19 February 2021Metastatic non-small-
cell lung
cancer		391White and Black ethnicity. Median age 65 years.Nivolumab + ipilimumab240 mg every 2 weeks + 1 mg/kg every 6 weeksNoYes12 of 16 (MINORS)
Reck et al.,
2016 [52]		Open-label, phase 3 trialNot specified19 September 2014 to 29 October 2015Advanced non-small-cell lung cancer305Ethnicity not specified. Median age 64.5 years.Pembrolizumab200 mg every 3 weeksYesNo2 of 5 (Jadad)
Rini et al.,
2011 [53]		Phase 1, open-label, multicenter, dose-escalation studyNot specifiedDecember 2006 to January 2009Metastatic renal cancer28Ethnicity not specified. Median age 60 years.Tremelimumab6 mg/kg, 10 mg/kg, or 15 mg/kg every 12 weeksYesNo11 of 16 (MINORS)
Seethapathy et al.,
2019 [54]		Retrospective observational cohort studyUSAMay 2011 to December 2016Not specified1016White, Black, Hispanic, Asian, and other ethnicities. Median age 65 years.Nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab + ipilimumabNot specifiedYesNo10 of 16 (MINORS)
Sharma et al., 2016 [55]Multicenter, open-label, two-stage, multi-arm, phase 1/2 studyFinland, Germany, Spain, UK, and USAJune 2014 to April 2015Metastatic urothelial carcinoma86White, Black or African American, Asian, and other ethnicities. Median age 65.5 years.Nivolumab3 mg/kg every 2 weeksYesNo11 of 16 (MINORS)
Spillane et al., 2020 [56]Retrospective observational studyUSA1 January 2011 to 31 August 2018Metastatic melanoma2407Ethnicity not specified Median age 73.75 years.Nivolumab, pembrolizumab, ipilimumab, nivolumab + ipilimumabNot specifiedYesNo10 of 16 (MINORS)
Sternberg et al., 2019 [57]Single-arm multicenter international open-label phase 3B safety studyEurope, Asia, South America, Australia, and CanadaNovember 2016 to March 2018Locally advanced or metastatic
urothelial or nonurothelial carcinoma of the urinary tract		997Ethnicity not specified. Median age 68 years.Atezolizumab1200 mg every 3 weeksYesNo10 of 16 (MINORS)
Sukari et al., 2019 [58]Retrospective studyUSA3 August 2011 to 31 August 2016Advanced non-small-cell lung cancer, renal cell carcinoma, Hodgkin’s lymphomas, head and neck squamous cell carcinoma, small-cell lung cancer168Ethnicity not specified. Median age 63 years.Nivolumab, pembrolizumabNot specifiedYesNo10 of 16 (MINORS)
Tachibana et al., 2021 [59]Retrospective studyJapanDecember 2015 to May 2020Advanced papillary renal cell carcinoma30Ethnicity not specified. Median age 67 years.Nivolumab + ipilimumabNot specifiedYesNo10 of 16 (MINORS)
Tio et al.,
2018 [60]		Retrospective cohort studyNot specifiedJuly 2014 to March 2017Advanced melanoma, urothelial carcinoma, renal cell carcinoma, mesothelioma, hepatocellular carcinoma, non-small-cell lung cancer, gastric cancer, glioblastoma46Ethnicity not specified. Median age 60 years.Nivolumab, pembrolizumab, atezolizumab, nivolumab + ipilimumab, pembrolizumab + ipilimumabNot specifiedYesYes9 of 16 (MINORS)
Tomita et al., 2019 [61] Phase 3, randomized, open-label studyJapan9 October 2012 to 14 March 2014Advanced renal cell carcinoma821Ethnicity and median age not specified.Nivolumab3 mg/kg every 2 weeksYesNo3 of 5 (Jadad)
Tykodi et al., 2022 [62]Non-randomized, open-label, multicohort, phase 3b/4 clinical trialUSANot specifiedAdvanced
non-clear-cell renal cell carcinoma		52Ethnicity not specified. Median age 64 years.Nivolumab + ipilimumab3 mg/kg + 1 mg/kg every 3 weeks NoYes9 of 16 (MINORS)
Vasudev et al.
2024 [63]		Phase 2, multicenter, randomized, controlled trialUnited KingdomMarch 2018 to January 2020Advanced renal cell carcinoma192Ethnicity and median age not specified.Nivolumab + ipilimumab3 mg/kg and 1 mg/kg i.v. every 12 weeksYesNo3 of 5 (Jadad)
Verhaart et al., 2021 [64]Retrospective analysisThe NetherlandsMarch 2016 to January 2018Advanced renal cell carcinoma264Ethnicity not specified. Median age 65 years.Nivolumab3 mg/kg every 2 weeksNoYes10 of 16 (MINORS)
Vogelzang et al., 2020 [65]Open-label phase 3b/4 studyUSADecember 2015 to December 2016Advanced non-clear-cell renal cell carcinoma44Ethnicity not specified Median age 62 years.Nivolumab240 mg every 2 weeksNoYes10 of 16 (MINORS)
Zhao et al.,
2021 [66] 		Retrospective studySingaporeNovember 2016 to April 2020Advanced renal cell carcinoma32Chinese, Indian, Malay, and Caucasian ethnicities. Median age 64 years.Nivolumab1.7 mg/kg and 2.7 mg/kg every 2 weeksNoYes9 of 16 (MINORS)
Zhou et al.
2024
[67]		Retrospective studyChinaDecember 2018 to October 2022Advanced lung, gastrointestinal, urogenital, other cancers904Ethnicity not specified. Median age 65 years.Anti-PD-1,
anti-PD-L1		Not specifiedYesNo9 of 16 (MINORS)
Table 2. Incidences of acute kidney injury (AKI) and nephritis in patients treated with ICIs in monotherapy and in combination. SEM, standard error of the mean.
Table 2. Incidences of acute kidney injury (AKI) and nephritis in patients treated with ICIs in monotherapy and in combination. SEM, standard error of the mean.
Anti-PD-1
Study IdentificationDrug (Posology)Patients IncludedAKI Incidence (%)Nephritis Incidence (%)
Abdelrahim et al., 2021 [19]Nivolumab (not described)3313.93
Antonia et al., 2016 [20]Nivolumab (3 mg/kg every 2 weeks)980.00
Atkins et al., 2023 [23]Nivolumab (240 mg every 2 weeks)355.71
Espi et al., 2021 [27]Nivolumab (not described)2303.91
Flippot et al., 2019 [28]Nivolumab (3 mg/kg every 2 weeks)734.11
Grimm et al., 2022 [31]Nivolumab
(3 mg/kg every 2 weeks, 240 mg every 2 weeks, or 480 mg every 4 weeks)		2281.32
Julien et al., 2020 [36]Nivolumab (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 10 mg/kg every 2 weeks, then all patients 3 mg/kg every 2 weeks)2620.760.00
McFarlane et al., 2020 [40]Nivolumab (240 mg every 2 weeks)97 3.09
Meraz-Muñoz et al., 2020 [41]Nivolumab (not described)549.26
Mourey et al., 2024 [43]Nivolumab (3 mg/kg every 2 weeks)7201.11
Rassy et al., 2022 [50]Nivolumab (3 mg/kg every 2 weeks)5110.39
Sharma et al., 2016 [55]Nivolumab (3 mg/kg every 2 weeks)781.28
Spillane et al., 2020 [56]Nivolumab (not described)3743.48
Tio et al., 2018 [60]Nivolumab (not described)128.33
Tomita et al., 2019 [61]Nivolumab (3 mg/kg every 2 weeks)4103.90
Verhaart et al., 2021 [64]Nivolumab (3 mg/kg every 2 weeks)264 2.27
Vogelzang et al., 2020 [65]Nivolumab (240 mg every 2 weeks)44 2.27
Zhao et al., 2021 [66]Nivolumab (1.7 mg/kg or 2.7 mg/kg every 2 weeks)32 3.13
Nivolumab
Incidence (weighted average ± SEM)		2.28 ± 0.031.57 ± 0.05
Abdelrahim et al., 2021 [19]Pembrolizumab (not described)4362.06
Espi et al., 2021 [27]Pembrolizumab (not described)705.71
Goldberg et al., 2020 [30]Pembrolizumab (10 mg/kg every 2 weeks)422.38
Meraz-Muñoz et al., 2020 [41]Pembrolizumab (not described)3658.33
Mok et al., 2019 [42]Pembrolizumab
(200 mg every 3 weeks)		6360.47
Powles et al., 2022 [48]Pembrolizumab
(200 mg every 3 weeks)		4884.100.20
Raghav et al., 2022 [49]Pembrolizumab
(200 mg every 3 weeks)		254.00
Reck et al., 2016 [52]Pembrolizumab
(200 mg every 3 weeks)		1541.95
Spillane et al., 2020 [56]Pembrolizumab (not described)5312.82
Tio et al., 2018 [60]Pembrolizumab (not described)21 4.76
Pembrolizumab
Incidence (weighted average ± SEM)		3.18 ± 0.140.39 ± 0.04
Cortazar et al., 2020 [11]Indeterminate (nivolumab/pembrolizumab)37733.69
Hofmann et al., 2016 [34]Indeterminate
(nivolumab 3 mg/kg every 2 weeks/pembrolizumab 2 mg/kg every 3 weeks)		496 0.40
Martini et al., 2018 [38]Indeterminate
anti-PD-1 (not described)		11 9.09
Noronha et al., 2021 [44]Indeterminate (nivolumab 3 mg/kg every 2 weeks/240 mg flat dose every 2 weeks/pembrolizumab 200 mg every 3 weeks)155 3.87
O’Reilly et al., 2020 [45]Indeterminate (nivolumab/pembrolizumab)17 5.88
Seethapathy et al., 2019 [54]Indeterminate (nivolumab/pembrolizumab)7012.28
Sukari et al., 2019 [58]Indeterminate (nivolumab/pembrolizumab)16848.81
Kanz et al., 2016 [37]Indeterminate (nivolumab/pembrolizumab)27 7.41
Zhou et al., 2024 [67]Indeterminate
anti-PD-1 (not described)		8844.98
Anti-PD-1 total incidence (weighted average ± SEM)5.32 ± 0.111.30 ± 0.04
Anti-PD-L1
Abdelrahim et al., 2021 [19]Atezolizumab (not described)220.00
Sternberg et al., 2019 [57]Atezolizumab (1200 mg every 3 weeks)9976.02
Tio et al., 2018 [60]Atezolizumab (not described)20.000.00
Atezolizumab
Incidence (weighted average ± SEM)		 5.88 ± 0.03
Apolo et al., 2020 [21]Avelumab (10 mg/kg every 2 weeks)24910.04
Powles et al., 2020 [47]Durvalumab (1500 mg every 4 weeks)3450.58
Massard et al., 2016 [39]Durvalumab (10 mg/kg every 2 weeks)611.64
Durvalumab
Incidence (weighted average ± SEM)		0.74 ± 0.02
Martini et al., 2018 [38]Indeterminate
anti-PD-L1 (not described)		1 0.00
Seethapathy et al., 2019 [54]Indeterminate (atezolizumab, avelumab, durvalumab)372.70
Zhou et al., 2024 [67]Indeterminate
anti-PD-L1 (not described)		2010.00
Anti-PD-L1 total incidence (weighted average ± SEM)5.25 ± 0.070.00 ± 0.00
Anti-CTLA-4
Abdelrahim et al., 2021 [19]Ipilimumab (not described)4748.23
Cortazar et al., 2020 [11]Ipilimumab (not described)9247.83
Meraz-Muñoz et al., 2020 [41]Ipilimumab (not described)21911.42
O’Reilly et al., 2020 [45]Ipilimumab (not described)59 3.39
Polkowska et al., 2019 [46]Ipilimumab (not described)3335.71
Seethapathy et al., 2019 [54]Ipilimumab (not described)2494.82
Spillane et al., 2020 [56]Ipilimumab (not described)5902.54
Ipilimumab
Incidence (weighted average ± SEM)		7.87 ± 0.21
Campbell et al., 2021 [25]Tremelimumab (10 mg/kg every 4 weeks)140.00
Rini et al., 2011 [53]Tremelimumab (6 mg/kg, 10 mg/kg, or 15 mg/kg every 12 weeks)911.11
Tremelimumab
Incidence (weighted average ± SEM)		4.35 ± 1.16
Anti-CTLA-4 total incidence (weighted average ± SEM)7.83 ± 0.21
Anti-PD-1 + Anti-CTLA-4
Abdelrahim et al., 2021 [19]Nivolumab + ipilimumab (not described)15911.32
Antonia et al., 2016 [20]Nivolumab (1 mg/kg) + ipilimumab (1 mg/kg), then nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) or nivolumab (3 mg/kg) + ipilimumab (1 mg/kg) every 3 weeks1150.87
Atkins et al., 2023 [23]Nivolumab 3 mg/kg + ipilimumab 1 mg/kg, every 3 weeks170.00
Blas et al., 2024 [24]Nivolumab + ipilimumab (not described)22943.922.44
Dizman et al., 2022 [26]Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks1010.00
George et al., 2022 [29]Nivolumab 6 mg/kg + ipilimumab 1 mg/kg every 8 weeks10611.321.89
Gul et al., 2020 [32]Nivolumab + ipilimumab (not described)45 2.22
Hammers et al., 2017 [33]Nivolumab (3 mg/kg) + ipilimumab (1mg/kg), nivolumab (1 mg/kg) + ipilimumab (3 mg/kg), or nivolumab (3 mg/kg) + ipilimumab (3 mg/kg) every 3 weeks10015.00
Izumi et al., 2023 [35]Nivolumab 240 mg + ipilimumab 1 mg/kg i.v. every 3 weeks1295.43
Meraz-Muñoz et al., 2020 [41]Nivolumab + ipilimumab (not described)2317.39
Ready et al., 2023 [51]Nivolumab 240 mg + ipilimumab 1 mg/kg every 6 weeks391 0.77
Seethapathy et al., 2019 [54]Nivolumab + ipilimumab (not described)293.45
Spillane et al., 2020 [56]Nivolumab + ipilimumab (not described)3890.77
Tachibana et al., 2021 [59]Nivolumab + ipilimumab (not described)306.66
Tio et al., 2018 [60]Nivolumab + ipilimumab (not described)60.000.00
Tykodi et al., 2022 [62]Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks52 3.85
Vasudev et al., 2024 [63]Nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 12 weeks1925.73
Nivolumab + ipilimumab
Incidence (weighted average ± SEM)		4.58 ± 0.052.21 ± 0.01
Abdelrahim et al., 2021 [19]Pembrolizumab + ipilimumab (not described)24221.07
Atkins et al., 2018 [22]Pembrolizumab (2 mg/kg) + ipilimumab (1 mg/kg) every 3 weeks220.00
Tio et al., 2018 [60]Pembrolizumab + ipilimumab (not described)50.000.00
Pembrolizumab + ipilimumab
Incidence (weighted average ± SEM)		18.96 ± 0.39
Anti-PD-1 + anti-CTLA-4 total incidence (weighted average ± SEM)5.58 ± 0.082.21 ± 0.01
Anti-PD-L1 + Anti-CTLA-4
Powles et al., 2020 [47]Durvalumab (1500 mg) + tremelimumab (75 mg) every 4 weeks3401.18
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Tascón, J.; Casanova, A.G.; Vicente-Vicente, L.; López-Hernández, F.J.; Morales, A.I. Nephrotoxicity of Immune Checkpoint Inhibitors in Single and Combination Therapy—A Systematic and Critical Review. Biomedicines 2025, 13, 711. https://doi.org/10.3390/biomedicines13030711

AMA Style

Tascón J, Casanova AG, Vicente-Vicente L, López-Hernández FJ, Morales AI. Nephrotoxicity of Immune Checkpoint Inhibitors in Single and Combination Therapy—A Systematic and Critical Review. Biomedicines. 2025; 13(3):711. https://doi.org/10.3390/biomedicines13030711

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Tascón, Javier, Alfredo G. Casanova, Laura Vicente-Vicente, Francisco J. López-Hernández, and Ana I. Morales. 2025. "Nephrotoxicity of Immune Checkpoint Inhibitors in Single and Combination Therapy—A Systematic and Critical Review" Biomedicines 13, no. 3: 711. https://doi.org/10.3390/biomedicines13030711

APA Style

Tascón, J., Casanova, A. G., Vicente-Vicente, L., López-Hernández, F. J., & Morales, A. I. (2025). Nephrotoxicity of Immune Checkpoint Inhibitors in Single and Combination Therapy—A Systematic and Critical Review. Biomedicines, 13(3), 711. https://doi.org/10.3390/biomedicines13030711

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