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  • Systematic Review
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13 March 2025

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

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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
Biomedicines2025, 13(3), 711;https://doi.org/10.3390/biomedicines13030711
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.
Figure 1. Flow chart of search and selection of studies carried out in accordance with the PRISMA guidelines.
Table 1. Descriptive characteristics of the studies included in the systematic review. Acute kidney injury (AKI).
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).
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.
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].
Figure 2. Signaling pathways affected in T lymphocytes due to the inhibition of check points. Blue arrows mean activation, and red lines mean inhibition.
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].
Figure 3. Mechanisms of kidney damage associated with immune checkpoint inhibitors.
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.

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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