Wen-Qing Lv
Jing-Yao Lu
Jun Li
Dao-Yuan Lv
Qi Ke- 1Department of Nephrology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
- 2Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
In recent years, immune checkpoint inhibitors (ICIs) have emerged as a critical component of hematological malignancies and solid malignant tumors therapy. However, clinical practice has revealed that these agents may induce immune-related adverse events (irAEs). Notably, renal irAEs stands out as a significant clinical concern, frequently necessitating treatment discontinuation and thereby enabling tumor progression. Renal irAEs constitutes a critical consideration for patients with cancer complicated by chronic kidney disease (CKD). This review systematically examines the immunologic pathogenesis of ICIs-induced renal disease, susceptibility genes, non-invasive biomarkers, and efficient intervention strategies. It further analyzes the critical considerations regarding renal irAEs that oncologists must address, based on real-world evidence from ICIs therapy in cancer patients with CKD, including those who are renal transplantation recipients or have end-stage renal disease (ESRD). Additionally, the promising targeted immunotherapy for malignant tumors is expected to improve both renal outcomes and survival prognosis in cancer patients.
1 Introduction
In recent years, immune checkpoint inhibitors (ICIs) have been widely used in the treatment of patients with metastatic renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, breast cancer, Hodgkin lymphoma, advanced melanoma, head and neck squamous cell carcinoma, as well as other malignancies, contributing to prolonged survival and improved life expectancy in this population (1). However, nephrotoxicity remains a significant safety concern associated with the administration of ICIs.
On one hand, immune checkpoint inhibitor-related acute kidney injury (ICIs-AKI) may impair the tolerance to anti-tumor therapies. Although ICIs are not renally metabolized (2), many other chemotherapeutic agents rely on renal excretion. On the other hand, kidney injury can lead to renal anemia, disturbances in fluid, electrolyte, and acid-base homeostasis, impaired immune function, and organ dysfunction due to accumulation of uremic toxins, thereby exacerbating the adverse effects of anticancer treatments. Therefore, early diagnosis and timely intervention for ICIs-AKI are of critical importance for improving renal outcomes and survival prognosis in cancer patients.
Currently, the identification and diagnosis of ICIs-AKI primarily rely on renal biopsy; however, the use of non-invasive biomarkers holds promise for early intervention and may contribute to improved renal outcomes. The non-invasive biomarkers may also reduce the necessity for renal biopsies, thus promoting faster patient recovery. Furthermore, ICIs-AKI may contribute to organ dysfunction and reduce survival rates in patients with malignant tumors, highlighting the critical need to identify susceptibility genes for early prediction.
Reduced estimated glomerular filtration rate (eGFR) has been significantly associated with increased risk of incident cancers in specific sites, including the renal tract (encompassing kidney, ureter, and bladder), oropharynx, respiratory system, hematologic tissues (such as myeloma and leukemia), skin, and abdominal solid organs (3, 4). In a cohort of 13,750 individuals diagnosed with concomitant chronic kidney disease (CKD), 2,758 (20.1%) subsequently developed cancer, with a median interval of 8.5 years between CKD diagnosis and cancer onset (5). In another study involving 431,263 participants from the UK Biobank—enrolled between 2007 and 2010 and without prior cancer history—41,745 new cancer cases and 11,764 cancer-related deaths were recorded over a median follow-up period of 11.3 years (6). Additionally, the 5-year cumulative incidence of any cancer among 482,510 incident hemodialysis patients was 9.48% (7). Up to 32% of cancer patients have CKD, and approximately two-thirds of this subgroup exhibit a glomerular filtration rate between 30 and 60 mL/min per 1.73 m², a range in which the selection of antineoplastic agents and dosage adjustments are typically required (8). Fortunately, the efficacy and safety of ICIs in patients with pre-existing renal dysfunction have been established (9, 10), which brings hope for cancer treatment in those with renal insufficiency. Given the adverse effects associated with ICIs administration, targeted delivery of ICIs may provide significant advantages by preserving renal function, maintaining survival rates, and improving quality of life during cancer therapy.
This review aims to provide a comprehensive overview of the epidemiological characteristics, pathogenesis, susceptibility genes, non-invasive biomarkers, therapeutic strategies, and prognosis associated with ICIs-AKI. Additionally, this article outlines the safety considerations of administering ICIs in cancer patients with CKD, including those who are renal transplantation recipients or have end-stage renal disease (ESRD), and reviews emerging targeted immunotherapeutic strategies designed to prevent renal irAEs.
2 Classification of ICIs and their anti-tumor mechanism
There are four types of ICIs currently approved for clinical use, as shown in Table 1.
Table 1. Classification of ICIs.
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is expressed on a variety of immune cells, including activated CD4+ and CD8+T cells, regulatory T cells, and tumor-infiltrating natural killer cells (11). Following T cell receptor activation and concurrent CD28-mediated co-stimulation, CTLA-4 is upregulated and translocated to the cell surface, where it competes with CD28 for binding to the critical co-stimulatory ligands CD80 and CD86, thereby delivering inhibitory signals that suppress T cell activation and proliferation (12). CTLA-4 inhibits IL-2 synthesis and cell cycle progression, and contributes to the termination of T-cell responses (13). Additionally, CTLA-4 can mediate the removal of immunostimulatory ligands from antigen-presenting cells through trogocytosis (14). Engagement of CTLA-4 on regulatory T cells enhances their immunosuppressive function. Thus, CTLA-4 inhibitors could enhance T cell activity by blocking CTLA-4, promoting T cell proliferation and cytokine secretion, activating self-reactive T cells, and consequently inducing T cell-mediated immune damage (15).
Programmed cell death protein 1 (PD-1) signaling is mediated by the tyrosine phosphatase SH2-containing protein tyrosine phos-phatase-1/2 (SHP-1/2), which dephosphorylates downstream molecules in the T cell receptor signaling pathway. Upon binding to its ligands—PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273), PD-1 inhibits kinases involved in T cell activation through recruitment of SHP-1 and SHP-2, thereby preventing self-tissue damage caused by excessive immune responses (14, 16). In addition to promoting the activity of these phosphatases, which dephosphorylate key signaling nodes essential for T cell co-stimulation, PD-1 has also been shown to suppress the RAS–extracellular signal-regulated kinase (ERK) pathway, a critical downstream cascade of TCR signaling (17). Tumor cells can evade immune surveillance by overexpressing PD-L1, which engages PD-1 on T cells and leads to suppression of T cell function, resulting in impaired recognition and elimination of tumor cells (18). Consequently, PD-1 inhibitors reverse T cell exhaustion and restore cytotoxic T cell function by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Therefore, when ICIs are used, the immune system loses its ability to self-regulate, leading to a breakdown in immunologic tolerance toward self-tissues and resulting in immune-related adverse events (irAEs) (19). (The antitumor mechanism of immune checkpoint inhibitors is illustrated in Figure 1).
Figure 1. The antitumor mechanism of immune checkpoint inhibitors. When anti-PD-1/PD-L1 antibodies block the interaction between PD-L1 and T cell PD-1 receptors, SHP-1/2 kinase is no longer recruited to inhibit TCR signaling. In the meanwhile, RAS gene can be enhanced. CTLA-4 competes with CD28 for binding to CD80/CD86 on antigen-presenting cells. Anti-CTLA-4 antibodies promote the interaction between CD28 and CD80/CD86, enhancing PI3K-AKT-mTOR as well as restoring the cell cycle of T cells (IL-2 involved). Similar to anti-PD-1/PD-L1, SHP-2 kinase is no longer recruited to inhibit TCR signaling. Meanwhile, these inhibitors block regulatory T cells from binding to ligand, thus suppressing their ability to inhibit excessive T cell activation. PD-1, Programmed cell death protein-1; PD-L1, Programmed cell death ligand1; CTLA4, Cytotoxic T lymphocyte-associated antigen-4; TCR, T cell receptor; Treg, regulatory T cell; MHC, Major histocompatibility complex; APC, Antigen-presenting cell; SHP, SH2 domain-containing protein-tyrosine phosphatase. Created in BioRender. lv, w. (2026) https://BioRender.com/lcnbhgk.
3 Epidemiology and clinical manifestation of ICIs-AKI
ICIs have significantly improved objective response rates and overall survival outcomes across multiple cancer types. However, ICIs are capable of inducing induce irAEs across multiple organ systems. A cohort study demonstrated that renal irAEs may co-occur with multiple extrarenal irAEs, particularly those affecting the endocrine and gastrointestinal systems (20). The overall incidence of irAEs associated with ICIs ranged from 45% to 83% (21) (any grade), with nephrotoxicity occurring in approximately 1% to 5% of cases, as well as ureteral and cystitis manifestations related to ICIs were rare (22, 23). Among patients with ICIs-AKI, more than one-third progressed to the most severe form of acute kidney injury, classified as AKI stage 3 (24, 25).
Over 80-90% of ICIs-AKI are acute tubulointerstitial nephritis (AIN) (25–27), characterized by CD4+ interstitial lymphocyte infiltration with eosinophils or phlogocyte. Data from the French Pharmacovigilance Database covering the period from 1985 to 2020 indicate that acute tubular necrosis (ATN) was reported in 28.6% (18/63) of patients, with ATN most frequently occurring concomitantly with AIN in 12 out of 18 cases (66.7%). However, preexisting renal susceptibility in elderly hypertensive individuals may be clinically significant, especially considering their frequent exposure to diuretics, renin-angiotensin system inhibitors, nonsteroidal anti-inflammatory drugs, and radiographic contrast agents—all of which are recognized risk factors for ATN, particularly in settings such as hypovolemia (25). Other renal pathologic types of ICIs-related kidney disease include various glomerulonephritis such as Pauci-immune Glomerulonephritis (including ANCA-positive or negative glomerulonephritis) (28), granulomatous arteritis (29), sarcoidosis-like reaction (30), Podocytopathy (primarily minimal change nephropathy), IgA nephropathy (31), membranous nephropathy, AA amyloidosis, C3 nephropathy, and anti-glomerular basement membrane disease (32). ICIs-related renal tubular acidosis and Fanconi syndrome has been documented in case reports. PD-1 checkpoint inhibitor-induced ureteritis and cystitis have also been reported in case studies, frequently resulting in misdiagnosis as urinary tract infections or obstructions (33). The renal pathological findings associated with ICIs-related renal disease are summarized in Table 2.
Table 2. The renal pathological findings associated with ICIs-related renal disease.
ICIs-AIN predominantly occurs 3–4 months after the initiation of ICIs therapy (2, 36), manifesting as an increase in serum creatinine exceeding 50% of baseline renal function, and is frequently accompanied by sterile pyuria, oliguria, and edema, although the classic “triple sign” (fever, rash, eosinophilia) remains uncommon (35). The patients with ICI- associated glomerulonephritis mostly present with proteinuria, hematuria, edema, and hypertension (34). Refractory hypokalemia, metabolic acidosis, and Fanconi syndrome have been reported in patients with immune-mediated renal tubular acidosis (37, 38). However, electrolyte disturbances should prompt exclusion of immune-mediated endocrine gland injury (39). More recently, urinary irritation, sterile pyuria, gross hematuria, hydronephrosis, and ureteral dilation have been described in association with immune-mediated ureteritis and cystitis (22, 23).
A low baseline estimated glomerular filtration rate had increased ICIs-AKI risk (40, 41).The concurrent use of nonsteroidal anti-inflammatory drugs, renin-angiotensin-aldosterone system inhibitors, fluindione (42), high-dose diuretics, and the occurrence of extra-renal irAEs were significantly associated with ICIs-AKI (43). Notably, proton pump inhibitor was identified as an independent risk factor for ICI-AIN (44). Furthermore, the administration of ICI agents may inadvertently predispose individuals to an adverse immunological state characterized by a heightened propensity for hypersensitivity reactions, potentially exacerbating other drug-associated AKI (45). Additionally, analysis of 19,609,804 irAEs reports from the FDA Adverse Event Reporting System database revealed an 80% to 160% increased risk of developing irAEs among individuals who experienced concomitant infections during treatment with ICIs. Proposed mechanisms by which infectious agents may contribute to irAEs include cryptic antigen presentation, bystander activation, molecular mimicry, epitope spreading, and infection-induced T-cell autoreactivity (46).
Notably, the risk of ICIs-AKI was significantly higher with combination therapy—specifically, the use of anti-PD-1/PD-L1 agents in conjunction with anti-CTLA-4 agents—than with monotherapy (47).
Therefore, ICIs-AKI, predominantly immune-mediated AIN, is not an uncommon irAE, particularly in the context of concomitant use of nephrotoxic agents, underlying infections, or combination therapy with anti-PD-1/PD-L1 and anti-CTLA-4. ICIs-AKI can also be accompanied by immune-mediated ureteritis and cystitis. Severe hypokalemia in the absence of immune-related endocrine injury should prompt consideration of renal tubular acidosis. In cases of significant proteinuria or steroid resistance, early evaluation of renal pathology is essential to optimize renal prognosis.
4 Pathogenesis of ICIs-AKI
Single-cell RNA sequencing combined with mass cytometry conducted in 162 patients experiencing irAEs demonstrated that a preexisting activated, autoimmune-like inflammatory milieu plays a key role in the development of irAEs during ICIs treatment. This pathogenic process is driven by three core mechanisms: increased plasmablast activation and elevated anti-nuclear antibody titers, upregulated interferon-γ (INF-γ)/C-X-C motif chemokine ligand (CXCL)10/C-X-C chemokine receptor (CXCR)3 signaling pathway, and amplified tumor necrosis factor (TNF) signaling activity (48). The transcriptomic assessment of kidney tissue indicated that the genes most markedly overexpressed in ICI-AIN were predominantly linked to pathways involved in antigen processing and presentation, as well as those driving T cell-dependent immune activation (49, 50). Furthermore, renal pathology from patients with ICI-AIN reveal an accumulation of resident macrophages, fibroblasts, and CD8+ T cells, where the resident macrophages display heightened expression of pro-inflammatory and pro-fibrotic markers. In mouse models, administration of anti-PD-1 treatment induces renal injury characterized by immune cell infiltration, tubular impairment, and fibrosis. Importantly, eliminating tissue-resident macrophages reduces the levels of CXCL9 and matrix metalloproteinase 12, thereby alleviating kidney damage (51). Analysis of urinary and plasma proteomes identified Janus kinase-signal transducer and activator of transcription (JAK-STAT) and TNF signaling pathways as key contributors to the development of ICI-AIN (52).
Several potential mechanisms underlying the pathophysiology of ICI-AKI are summarized below (Figure 2).
Figure 2. The proposed mechanisms underlying ICIs-induced AKI. Activated T-cells and inflammatory cytokines: T cells are activated as a result of disrupted immune tolerance—through mechanisms such as cryptic antigen presentation, bystander activation, molecular mimicry, and epitope spreading—leading to the subsequent release of inflammatory cytokines. Protective effect of PD-L1 on proximal renal tubules: Anti-PD-1/PD-L1 antibodies can block the interaction between PD-L1 expressed on renal tubular cells and PD-1 present on T cells, thereby disrupting immune tolerance and leading to immune-mediated renal tubular injury. Activated hypersensitivity reactions: MS4A2 (membrane-spanning 4-domains subfamily A member 2), IL4 (interleukin-4), and CCL26 (C-C motif chemokine ligand 26)—genes known to be involved in allergic response pathways, including those linked to immunoglobulin E (IgE), mast cells, eosinophils, and basophils. Activated B cells produce Aabs: T cells release signals that activate B cells, which then produce autoantibodies that damage kidney tissue. Activated complement pathway: Autoantibodies and renal autoantigens form antigen-antibody complexes, which activate the complement pathway. DC, Dendritic cells; MAC, Membrane attack complex; TCR, T cell receptor; MHC, Major histocompatibility complex. PAMPs, Pathogen-Associated Molecular Patterns. Created in BioRender. lv, w. (2026) https://BioRender.com/sgsw389.
4.1 Active T-cells and inflammatory cytokines
The two immune checkpoints, CTLA-4 and PD-1/PD-L1, play complementary roles in maintaining peripheral immune tolerance (53). The blockade of either pathways removes the multilayered inhibition on self-reactive T cells, thereby enabling direct CD4+ or CD8+ T cell-mediated attacks on autologous tissues (54)—including renal tubular epithelium-and promoting cytokine—driven inflammatory amplification, ultimately resulting in immune-mediated AIN (55, 56).
Activated T cells can induce the release of inflammatory cytokines, such as IFN-γ and interleukin-21 (IL-21), which may play a role in the pathogenesis of ANCA-associated vasculitis (34).
Moreover, studies have shown that T lymphocyte infiltration is the predominant histopathological feature in the bladder tissues of most patients with ICIs-related ureteral cystitis (33). This inflammation of the urinary tract may occur concurrently with renal immune-related adverse events, suggesting a potential role of T cells in the pathogenesis of ICI-associated urinary system injury.
4.2 Activated hypersensitivity reactions
Transcriptomic analysis of renal tissue revealed that the genes most markedly overexpressed in ICI-AIN encompassed MS4A2 (membrane-spanning 4-domains subfamily A member 2), IL4 (interleukin-4), and CCL26 (C-C motif chemokine ligand 26)—genes known to be involved in allergic response pathways, including those linked to immunoglobulin E (IgE), mast cells, eosinophils, and basophils (49). Therefore, ICIs-AIN may be induced or may facilitate acute renal tubulointerstitial injury caused by the concomitant use of nephrotoxic agents and underlying infections.
4.3 Autoantibody produced by activated B cells
T cells deliver helper signals that activate B cells, which subsequently produce autoantibody (Aabs) targeting autoantigens on tubular epithelial cells, mesangial cells, or podocytes (54). For example, patients treated with ipilimumab have been reported to develop nephrotic syndrome and lupus-like immune complex glomerular lesions, with the concurrent presence of anti-CTLA-4 antibodies, anti-double-stranded DNA antibodies, and antinuclear antibodies (57). Relevantly, ipilimumab treatment was associated to a lupus-like glomerulopathy, and to serum circulating levels of anti dsDNA and anti-nuclear antigen antibodies closely resembling the autoimmune lupus nephritis phenotype (58).
4.4 Protective effect of PD-L1 on proximal renal tubules
PD-L1 is constitutively expressed at low levels in the proximal renal tubules of normal kidney tissue. In vitro studies have shown that IFN-γ can upregulate PD-L1 expression in human proximal renal tubule epithelial cells (59, 60). The interaction between PD-L1 on renal tubular cells and PD-1 on T cells contributes to immune tolerance by protecting tubular cells from T cell-mediated immune damage (59, 61). However, binding of monoclonal antibodies to PD-L1 expressed on renal tubules may disrupt this protective mechanism, potentially resulting in tubular injury.
4.5 Activation of the complement pathway
ICIs may induce disorders of the complement system, such as the previously reported cases involving anti-C3b antibodies and C3 glomerulopathy (34). The Aabs mentioned may bind to autoantigens, subsequently forming antigen-antibody complexes that deposit in the glomeruli, thereby activating the complement cascade. T cell-mediated immune responses and complement activation represent the primary immunopathological mechanisms underlying drug-induced AIN (62). The role of complement activation in the pathogenesis of ICIs–induced glomerulonephropathy and AIN warrants further investigation.
Collectively, it was previously believed that activated T cells, resulting from disrupted immune tolerance-through mechanisms such as cryptic antigen presentation, bystander activation, molecular mimicry, and epitope spreading—and the subsequent release of inflammatory cytokines play a crucial role in the pathogenesis of ICIs-AIN. Emerging genetic and proteomic evidence has demonstrated that resident macrophages exhibiting heightened expression of pro-inflammatory and pro-fibrotic characteristics also contribute to disease development. The pathogenesis of glomerulonephritis in patients receiving ICIs needs further research; however, activation of T cells, B cells, and the complement cascade may collectively induce injury to intrinsic glomerular cells.
5 Noninvasive methods for the prediction or diagnosis for ICIs-AKI
Renal pathology obtained through renal biopsy serves as the gold standard for diagnosing renal irAEs. Given the clinical condition of patients with advanced malignancies, renal biopsy may not be a feasible or timely diagnostic approach. Therefore, the identification of non-invasive biomarkers is of critical importance, particularly in patients presenting with contraindications to renal biopsy, such as a solitary kidney or thrombocytopenia. Predictive biomarkers are listed in Table 3.
Table 3. Predictive biomarkers for ICIs-AKI.
5.1 Cytokines and their receptors
Several non-invasive biomarkers of ICIs-AKI have been reported in recent years, primarily including cytokines and their corresponding receptors. Urinary CXCL9, a chemokine associated with IFN-γ-related genes, is considered a promising novel biomarker for differentiating ICIs-AIN from other etiologies of AKI (63, 75). Recent studies demonstrated that elevated urinary levels of TNF-α (65), IL-9 (64) and IL-10 (65) may serve as potential biomarkers for differentiating ICIs–AIN from other etiologies of AKI. Urine proteomic analysis identified a biomarker signature—urinary IL-5 and urinary Fas—that achieved an area under the curve of 0.94 for the diagnosis of ICI-AIN (52).
The diagnostic specificity for ICI-AKI was 100% when the levels of soluble interleukin-2 receptor (sIL-2R) was more than 1.75 times the upper limit of normal (75). However, sIL-2R was also elevated in hematological malignancies and renal cell carcinoma (68). Therefore, these conditions should be clinically excluded when interpreting sIL-2R as a biomarker. IL-17 is primarily secreted by Th17 CD4+ cells, which are potent mediators of autoimmunity and are regulated by CTLA-4 (76). It has been reported not only to be associated with an increased incidence of irAEs, but also to be overexpressed during AKI (59), suggesting its potential as a promising biomarker for ICIs-AKI (77). Other cytokines, including urinary CXCL11, IL-6, and monocyte chemotactic protein-1 (66, 67), are currently under investigation for their potential to enable early identification of ICIs-AKI.
5.2 Immune cells
An elevation in urinary soluble CD163 levels was also observed during anti-PD-1 treatment in patients with melanoma (69). The predominance of urinary M1 macrophages is indicative of acute kidney injury secondary to AIN, whereas the dominance of urinary M2 macrophages may serve as a potential biomarker for disease progression, particularly in cases of crescentic glomerulonephritis. Urinary macrophage subtypes may therefore aid in distinguishing between renal interstitial and glomerular lesions (77). The detection rate of eosinophiluria is relatively low; however, its presence may enhance the pre-test probability of ICI-AIN (22, 78).
Compared with patients who did not develop ICI-AKI following ICI therapy, those with ICIs–AKI exhibited significantly lower absolute counts of CD8+ T cells and naïve CD45RA+CD8+ T cells in peripheral blood, along with reduced absolute counts of memory-type CD27+CD19+ B cells and a trend toward relative expansion of plasmablasts (68). Urinary T cells have been identified in patients with ICIs–AKI (ICI-AIN or Vasculitis), and these cells are typically clonally identical to renal T cell infiltrates, suggesting that urinary T cells may serve as a noninvasive biomarker for ICI-induced immune nephritis (72).
5.3 Other biomarkers
Serum C-reactive protein (CRP) and the urinary retinol-binding protein-to-creatinine ratio (uRBP/Cr) have been identified as potential biomarkers for differentiating ICIs-AKI from other causes of AKI (74). Although uRBP/Cr and CRP levels may also be elevated in other forms of tubular injury, the concurrent elevation of both CRP and uRBP/Cr in the absence of identifiable infections or inflammatory conditions may indicate the presence of ICI-AIN. Conversely, if both CRP and uRBP/Cr levels remain within normal ranges without requiring immunosuppressive therapy, the probability of ICIs-AKI is markedly diminished (78).
Urinary soluble PD-1 and serum soluble PD-1 levels are significantly elevated in patients with ICI-AIN compared to those with acute tubular necrosis. In cancer patients, a urinary soluble PD-1 level below 129.3 pg/mL demonstrated a sensitivity of 71.43% and a specificity of 94.44% in differentiating acute tubular necrosis from ICI-AIN. Therefore, both urinary and serum soluble PD-1 may serve as potential biomarkers for distinguishing acute interstitial nephritis from acute tubular necrosis in oncology patients (73).
Granzyme B (a T cell activation marker)-specific positron emission tomography (PET) imaging demonstrated elevated renal uptake associated with renal irAEs, which markedly decreased following administration of the immunosuppressive agent dexamethasone. Histological analysis confirmed the presence of granzyme B and immune cell infiltrates, showing a strong correlation with increased PET signal intensity. These findings suggest that granzyme B-targeted PET imaging could serve as a potential non-invasive approach for detecting renal involvement in irAEs. The presence of granzyme B was also confirmed in renal samples from patients that presented with clinical renal irAEs. Whether renal granzyme B expression can serve as a biomarker of renal irAE need further research (79).
Furthermore, renal imaging detection may assist in the diagnosis of ICI-AIN. Shruti et al. reported that patients with ICI-AIN, including 3 renal biopsy-confirmed cases among 9 patients, exhibited a marked increase in mean standardized uptake value on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography—computed tomography (FDG-PET/CT) from baseline to the time of AIN diagnosis, compared with other patients (80). Bilateral renal enlargement, new or increasing perinephric stranding, and bilateral wedge-shaped cortical areas of hypoenhancement were identified as characteristic imaging features of ICI-AIN (81).
Collectively, urinary CXCL9 and TNF-α are considered promising novel biomarkers for differentiating ICIs-AIN from other forms of AKI. Granzyme B -specific PET imaging has demonstrated the presence of granzyme B and immune cell infiltrates associated with renal irAEs, representing a promising non-invasive imaging approach for assessing the severity of activated immune cell infiltration in the kidney. However, these biomarkers remain in the clinical research phase and require further validation through clinical application.
5.4 Susceptibility gene
The identification of predisposing genetic factors may help prevent the occurrence of renal irAEs in high-risk patients with malignancy. One study confirmed that differentially expressed genes and their enriched pathways identified in CD4+ T cells (FOS, RPS26, JUN) and CD8+ T cells (RPS26, TRBV25-1, JUN) play important roles in the development of renal irAEs events associated with anti-PD-1 therapy (50). The rs16957301 variant in the PCCA gene may serve as a risk marker for ICI-AKI in Caucasian populations (82). However, none of the forementioned studies on the susceptibility genes associated with ICI-AKI were based on renal pathological confirmation. IFI27, an IFN-α–induced transcript, was identified and validated as a novel biomarker for differentiating ICI–associated T cell–mediated rejection from ICI-AIN (49).
In addition to renal adverse events, the anti-CTLA4 induced irAEs were associated with a genetic variant associated with high SYK expression. This genetic profile could serve as a baseline biomarker for risk of severe irAEs (grade 3-5) (83). A retrospective study reveals that the existence of the PDCD1 PD-1.6 polymorphism (G allele) was associated with the occurrence of severe and multiple irAEs in patients with mRCC (84). A genetic screening for irAEs (including nephrotoxicity) revealed that the C allele of MAPK1 rs3810610 was a risk predictor for irAEs of all grades. The A allele of ADAD1 rs17388568 increased the risk of high-grade irAEs (50). These susceptibility gene associated with extrarenal organs are anticipated to represent a promising research direction for renal irAEs.
Collectively, limited evidence currently exists regarding susceptibility genes associated with renal irAEs. These findings have not yet been incorporated into clinical practice, as further studies are required to validate the association and investigate potential risks across diverse populations. Further research is needed to identify these genetic factors and their role in renal irAEs, with the aim of preventing such complications in susceptible populations.
6 Treatment and prognosis of ICIs-AKI
Patients with ICIs-AKI have a worse renal prognosis compared to those with AKI attributable to other etiologies (85). The primary therapeutic regimen includes discontinuation of ICIs and suspected nephrotoxic drugs (35). Clinical studies on ICIs-AKI therapy are shown in Table 4.
Table 4. Clinical studies on the management of ICIs-AKI.
With regard to discontinuation of ICIs, it is crucial to avoid unnecessary discontinuation of ICIs, particularly in the absence of alternative treatment options, and to guide therapy based on findings from renal biopsy or non-invasive urinary biomarker as discussed above, in future clinical practice (21). For patients with stage 2 AKI or higher severity, ICI should be discontinued immediately (94).
Glucocorticoids are recommended as the first-line treatment for ICIs-AIN. Earlier initiation of glucocorticoid therapy (within three days of onset), is more than twice as likely to be associated with renal recovery compared to delayed initiation, and this association is significantly correlated with improved overall survival outcomes (32, 94). Prednisone initiation is recommended at a dosage range of 0.8 to 1 mg/kg in patients diagnosed with ICIs-AKI (suspected ICIs-AIN without confirmation by renal pathology) (94). For patients with AKI stage 3, oral corticosteroids are recommended as a sequential therapy following intravenous pulse corticosteroid therapy. A slow corticosteroid tapering regimen is recommended to reduce the risk of disease recurrence, given the prolonged half-life of ICI and their association with sustained T cell activity (35). The total duration of glucocorticoid treatment is variable but ranges from 6 to 8 weeks in most studies (94). A multicenter retrospective cohort analysis of immunotherapy-naïve patients with advanced melanoma receiving combination therapy with ipilimumab and nivolumab, along with a smaller group treated with nivolumab and ipilimumab, demonstrated that a peak steroid dose exceeding 80 mg other than cumulative steroid dose was significantly linked to worse progression-free survival and overall survival (95). However, prolonged corticosteroid therapy may lead to adverse events, including infections, steroid-induced diabetes mellitus, and skeletal complications. Early discontinuation of corticosteroids may enable eligible patients to undergo rechallenge with ICIs therapy sooner, thereby improving the overall management of malignancy.
Some studies have shown that short-course corticosteroid regimen (≤28 days) does not increase the risk of recurrence or mortality compared with long-course regimen (29–84 days), and renal function recovery is comparable between the two groups (87). However, this therapeutic approach requires validation through randomized controlled trials and may not be generalizable to non-ICIs-AIN pathological subtypes.
Although AIN, a common renal irAEs induced by ICIs, is generally responsive to glucocorticoid therapy, approximately 20% of long-term survivors develop CKD or experience a significant decline in renal function. Furthermore, data from a large cohort study indicate that 1.9% of patients are steroid-refractory or could not be successfully tapered off the dosage, otherwise adverse reactions would recur (96). This is attributed to incomplete recovery from AKI, subclinical interstitial nephritis, and recurrent renal insults (40).
There remains limited clinical evidence to guide the management of steroid-refractory ICI-AIN. Recent case series indicate that infliximab may be an effective therapeutic option for patients with relapsing or refractory ICIs-AIN (90). SM Herrmann et al. reports case series in which serial monitoring of noninvasive biomarkers was used to direct steroid-sparing therapy with infliximab for biopsy-proven ICIs-AIN.
They trend a cytokine panel prior to each infliximab infusion to monitor TNF-α levels, which are frequently elevated at baseline and may correlate with treatment response. Biomarkers (TNF-α/Cr, CXCL9/Cr, RBP/Cr) were utilized to guide the timing and duration of therapy prior to the occurrence of significant elevations in serum creatinine (97). Prednisone is recommended to be given concomitantly with infliximab at least for the first 2 weeks, until TNF-α blockade is effective in patients with steroid-dependent ICIs-AIN (78, 97).
Janus kinase (JAK) signaling contributes to the pathophysiology of irAEs by establishing and perpetuating a pro-inflammatory environment. Tofacitinib, an oral JAK inhibitor, has enabled successful steroid tapering and may represent a therapeutic option for refractory ICIs-AIN (93). However, we should use it cautiously because it has been associated with adverse cardiovascular outcomes and secondary cancers (94). Mycophenolate mofetil also holds potential in treating ICIs-AIN (27, 32).
Case series have demonstrated that tocilizumab has a favorable safety profile and efficacy in the treatment of irAEs in patients with melanoma and lung cancer (98). However, there have been no reported cases of tocilizumab use in the treatment of refractory ICIs-AIN. Given the involvement of inflammatory cytokines in ICIs-AKI, the efficacy and safety of biologic agents targeting specific cytokines—such as inhibitors of IL-6, IL-17, IL-23, and IL-12—in the management of renal irAEs, particularly steroid-resistant cases, require further investigation (98).
Rituximab is recommended in patients who develop ICIs-related renal vasculitis (91). Complement inhibitors may represent a viable therapeutic option for patients with thrombotic microangiopathy caused by complement activation (94).
The use of azathioprine, cyclophosphamide, or cyclosporine in the management of ICI-AIN is currently not recommended due to the limited availability of evidence-based clinical data (94). Limited evidence demonstrated that immunosuppressive therapy may potentially accelerate the progression of underlying malignancies, thereby posing a critical challenge in the management of such patients (79). Plasmapheresis which aims to clear up Aabs has been reported to successfully treat critically ill patients with renal irAEs in case report (26).
Currently, glucocorticoids are the first-line treatment for ICI-AIN, but there exists drug tolerance and side effects. Therefore, further clinical investigation is warranted to establish the optimal dosage and duration of immunosuppressive therapy that effectively balances therapeutic efficacy with the risk of malignancy progression in patients experiencing renal irAEs. Based on the pathogenesis of ICI-AKI, further clinical studies are needed to comprehensively evaluate the efficacy and safety profiles of immunosuppressive and biologic agents, including infliximab, tocilizumab, and abatacept, in the context of renal irAEs.
The prognosis of ICIs-AKI involves two critical dimensions: recovery of renal function and survival outcomes associated with the underlying malignancy. Consequently, there is significant clinical concern regarding whether reinitiating ICI therapy may lead to exacerbated renal injury or precipitate severe irAEs. Fortunately, several studies proved that ICI rechallenge is generally associated with milder toxicity compared to the initial course of ICI therapy. Patients who experience disease progression following discontinuation of ICI treatment, or those who stopped therapy due to irAEs, may derive clinical benefit from reintroducing ICIs. While reinitiating ICI therapy seems feasible and tolerable under careful surveillance, the decision should be carefully considered by weighing the potential benefits of rechallenge, patient-specific comorbidities, and the risk of recurrence of irAEs (99–101).
7 The use of ICIs in patients with CKD and concomitant malignancy
The primary metabolic pathway of ICIs involves intracellular uptake and lysosomal degradation, which occurs via phagocytosis or target antigen-mediated drug disposition (102). Since ICIs are not primarily cleared through the renal system, the theoretical risk of drug accumulation in patients with CKD is considered to be low (102). A retrospective cohort study found no significant difference in overall treatment-related or irAEs between patients with normal renal function and those with impaired renal function (103). ICIs have demonstrated comparable efficacy to other antineoplastic therapies. The median treatment duration in patients with CKD and renal cell carcinoma was similar to that observed in individuals with normal eGFR (104).
ICI has not been linked to a higher risk of AKI or renal failure in individuals with advanced CKD (10). A small-sample study suggested that the overall incidence of irAEs among patients undergoing maintenance hemodialysis or peritoneal dialysis (32%) may be lower than that reported in the general population (40—60%) during ICI therapy (9).
Although patients undergoing hemodialysis exhibit compromised immune function as a result of diminished cell-mediated and humoral immune responses, clinical evidence indicates that the pembrolizumab, a PD-1 inhibitor, retains the capacity to effectively activating anti-tumor immune responses (105). Notably, no irAEs were observed during the 34-week treatment period or after discontinuation of therapy (105). Moreover, given the high molecular weight of ICIs, the likelihood of these agents being removed by dialysis is remarkably low (9); this theoretically poses no risk to the drug’s half-life or therapeutic efficacy.
In a large cohort study, the skin and gastrointestinal tract were the most commonly affected organ systems in patients with CKD or ESRD, consistent with the pattern observed in the general population (10, 102). Notably, the relatively high incidence of hematological adverse events in patients with ESRD contrasts with the low frequency reported in the general population. However, given that anemia and other hematologic abnormalities in patients undergoing dialysis (hemodialysis or peritoneal dialysis) may have multifactorial etiologies, this observation does not necessarily indicate that ICIs pose increased hematological risks in patients with ESRD (102).
A series of case reports has demonstrated that ICIs can be administered to patients undergoing dialysis—4 (21%) receiving peritoneal dialysis and 15 (79%) hemodialysis—at standard doses, with 42% of patients achieving long-term survival (>12 months) or remission, particularly among those with melanoma (9).
Hemodialysis patients inherently face a high risk of infection due to impaired immune function. Moreover, corticosteroid therapy required for the management of irAEs further increases susceptibility to infection (106), including viral or bacterial pneumonia and Pneumocystis jirovecii pneumonia (107). Therefore, close monitoring of lymphocyte counts, markers of humoral immunity, and infection-related biomarkers is essential during ICI therapy to enable early detection, prevention, and management of infectious complications.
Collectively, ICIs are neither renally cleared nor dialyzable, and can therefore be administered to patients with CKD or even ESRD at standard doses with maintained efficacy and safety. However, irAEs should be closely monitored in CKD patients, particularly hematological adverse events in those with ESRD. Notably, corticosteroid therapy used to manage irAEs may further increase the risk of infection.
8 The use of ICIs in kidney transplant recipients
Kidney transplantation is the most effective treatment for advanced kidney disease. Kidney transplant recipients (KTRs) have been observed to exhibit a two-to four-fold higher cancer incidence compared to those without a history of transplantation (108, 109). A nationwide cohort study using data from the Scottish Renal Registry, the Scottish Cancer Registry, and hospitalization records from 1997 to 2021 reported that the incidence of cancer among KTRs under the age of 40 was seven times higher than that in the general population; this elevated risk decreased to three times the baseline level among KTRs over the age of 60 (110). During periods of functional kidney grafts, the occurrence of infection-associated and immune-related malignancies is elevated relative to non-functional phases. These cancers include Kaposi sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, lip cancer, non-epithelial skin cancers, and kidney cancer (111). Additionally, colorectal cancer has emerged as a malignancy of particular concern among KTRs (112). Notably, cancer ranks as the second most common cause of mortality in KTRs. Among 38,130 patients undergoing their first kidney transplantation, 970 (2.5%) were identified with incident cancer, and 38% of these individuals died within four years following cancer detection (113). The absolute risk of death with a functioning graft was notably elevated among KTRs diagnosed with lung cancer (78%), post-transplant lymphoproliferative disorder (38%), melanoma (35%), or colorectal cancer (49%) (113).
The administration of ICIs in this population remains complex due to concerns about reduced therapeutic effectiveness under concurrent immunosuppression, as well as an increased likelihood of allograft rejection. Recent case series have reported an objective response rate ranging from 27% to 45% (114–116), with the incidence of acute rejection in KTRs receiving ICIs estimated between 30% and 48% (116–118). Notably, allograft loss occurs in 65% to 70% of those experiencing rejection (116–118). A meta-analysis of 128 studies encompassing 243 KTRs treated with ICIs reported overall survival rates were 41.6% at 250 days and 16.4% at 500 days; and progression-free survival rates were 31.0% at 250 days and 11.3% at 500 days (119). Therefore, early diagnosis of rejection in kidney transplantation is critical for preserving renal function and has a significant impact on the prognosis of KTRs with cancer receiving ICI therapy. Kidney allograft rejection typically occurs approximately 3 weeks after the initiation of ICIs, in contrast to ICIs-AIN, which tends to develop around 14 weeks following ICI initiation (115, 116, 120). Two biomarkers—donor-derived cell-free DNA (dd-cfDNA) (121) and urinary levels of CXCL-10 (122)—may serve as tools for the early detection of acute allograft rejection in KTRs undergoing ICIs therapy. An increased proportion of CD45RA-expressing effector memory T cells among CD8+ T cells has been associated with a higher risk of graft failure (123). In contrast, a distinct expansion of granzyme B-producing regulatory B cells has been observed in KTRs exhibiting operational tolerance, along with a robust B-cell signature linked to a low risk of graft failure (124). Kidney allograft rejection is definitively diagnosed through biopsy, which remains the gold standard in clinical practice. Among reported cases confirmed by biopsy to have kidney allograft rejection, T-cell mediated rejection is the most commonly observed form, while combined mixed T-cell and antibody-mediated rejection can also occur (115, 116). Elevated renal expression of the IFI27 gene (interferon-alpha inducible protein 27) has been identified as a potential biomarker for distinguishing kidney allograft rejection from those with ICIs-AIN (49).
Current clinical practice suggested that a dynamic steroid regimen combined with conversion to mTOR inhibitors may be associated with a reduced risk of kidney allograft rejection while simultaneously enabling an antitumor response (116, 125–127). In addition, anti-IL-6 therapy is currently under investigation in randomized controlled trials for the treatment of T-cell-mediated rejection and antibody-mediated rejection, given that IL-6 is a key proinflammatory cytokine whose elevated levels have been associated with irAEs and poorer oncologic outcomes in patients receiving ICIs therapy (128, 129).
Collectively, given the high incidence and mortality of malignant tumors among KTRs, early tumor screening should be prioritized to enable timely diagnosis and intervention. For those who develop malignancies post-transplantation, a comprehensive assessment of risks and benefits is essential prior to initiating ICI therapy. During ICI treatment, regular monitoring of biomarkers associated with graft rejection is recommended to ensure effective antitumor activity while preserving allograft function. Future research should focus on identifying non-invasive biomarkers capable of differentiating acute rejection from ICI-AIN at an early stage. To achieve sustained tumor control without compromising transplanted kidney function, optimal individualized strategies combining optimal immunosuppressive regimen and immunotherapeutic therapy require further validation through clinical studies.
9 Targeted immunotherapy with the potential to reduce the risk of irAEs
Although ICIs can induce antitumor responses, their simultaneous activation of the immune system may trigger immune-mediated adverse reactions involving multiple organ systems, potentially resulting in life-threatening complications. Therefore, the targeted delivery of ICIs may not only inhibit malignancy progression but also hold the potential to reduce irAEs.
PD-1 transfected macrophage membrane-derived nanoparticles (PMMNPs) can target both T cells and macrophages, selectively accumulating in tumor tissues to reduce the required dose of ICIs and associated side effects while preserving therapeutic efficacy. Animal studies have demonstrated that intravenous administration of PMMNPs does not induce hepatic and renal toxicity in vivo (130). Researchers have developed calcium phosphate nanoparticles for the co-delivery of anti-PD-L1 and CD73 inhibitors. This delivery strategy circumvents irAEs associated with anti-PD-L1 therapy while significantly enhancing treatment efficacy and reducing the required dosage by twenty-fold (131).
Another study functionalized the surface of Glycyrrhiza uralensis Fisch root-derived nanovesicles with antitumor properties by conjugating a PD-L1 antibody and encapsulating the STING pathway agonist DMXAA, thereby constructing a multifunctional, plant-derived nanocapsule designated GP@DMX NV. This system is capable of specifically targeting melanoma cells with elevated PD-L1 expression, thereby enabling efficient delivery of immunostimulatory agents to tumor sites.
STING agonists are essential for the type I interferon response, which is a prerequisite for antigen-presenting cells to differentiate and kill tumor cells (132). Furthermore, STING agonists demonstrate synergistic antitumor effects when combined with PD-1 inhibitors (133, 134). Although activation of the mtDNA-cGAS-STING signaling pathway contributes to ferroptosis in AKI (135, 136), glycyrrhiza uralensis fisch roots-derived nanovesicles can serve as delivery vehicles to promote intratumoral accumulation of STING agonists, thereby enhancing dendritic cell maturation while mitigating renal damage. This approach not only improves therapeutic efficacy but also reduces the toxic side effects associated with conventional combination therapies, demonstrating enhanced biosafety and biocompatibility (137).
A gelase-responsive nanoparticle enables targeted delivery of anti-PD-1 and the TGF-β receptor I inhibitor galunisertib to tumor tissues, effectively suppressing malignancy progression without observed renal side-effects (138).
Professor Lin’s team designed a novel nanoscale coordination polymer particle, Cu/TI, loaded with Cu²+ and PD-L1 inhibitor derivatives. The particle enables precise delivery of anticancer metal ions and small-molecule ICIs while exhibiting favorable biocompatibility (139).
In addition to nanoparticles, targeted delivery can also be achieved using engineered yeast. When the ICI variant was expressed in Saccharomyces boulardii, the engineered probiotic yeast effectively targeted the PD-1-PD-L1 axis and significantly reduced intestinal tumor burden in a murine model of colorectal cancer resistant to conventional ICI therapy, while simultaneously inhibiting tissue dissemination and tumor infiltration (140).
Collectively, various engineered materials have demonstrated significant potential for tumor-targeted drug delivery and enhanced antitumor efficacy. Although preclinical studies in animal models have confirmed the safety and effectiveness of these agents, further research and rigorous validation are necessary before clinical translation can be achieved. Research on targeted immunotherapy, as presented in Table 5.
Table 5. Research on targeted immunotherapy.
10 Conclusion
Collectively, renal immune-related adverse events (irAEs) are common among cancer patients receiving immunotherapy. Early diagnosis and timely, effective interventions can improve renal outcomes and overall survival. Urinary and serum biomarkers, along with certain imaging modalities, represent promising non-invasive approaches for the detection of immune checkpoint inhibitor (ICI) -associated tubulointerstitial nephritis (AIN). Moreover, the identification of genetic polymorphisms may help detect individuals carrying susceptible genotypes for renal irAEs, although this requires further investigation. Corticosteroids are the first-line treatment for ICI-AIN. Further clinical studies are warranted to determine the optimal dosage and duration of immunosuppressive therapy that balances efficacy with the risk of tumor progression in patients with renal irAEs. Infliximab is safe and effective in steroid-resistant cases. Additional research is needed to comprehensively evaluate the efficacy and safety of immunosuppressive and biologic agents—including tocilizumab, and Janus kinase inhibitors—in managing renal irAEs. Although ICI rechallenge appears safe under close monitoring, the decision should be individualized, weighing the potential benefits against patient comorbidities and the risk of irAE recurrence. Although ICIs are not renally excreted, severe kidney injury may compromise tolerance to subsequent chemotherapy or immunotherapy regimens. For renal transplant recipients, close monitoring is essential to prevent allograft rejection induced by ICIs. Biomarkers, along with a dynamic steroid regimen and conversion to mTOR inhibitors, represent critical strategies for mitigating the risk of kidney allograft rejection while simultaneously enabling an antitumor response. Furthermore, targeted immunotherapies for malignancies hold promise not only in controlling tumor progression but also in minimizing the incidence and severity of irAEs, thereby improving renal outcomes and survival prognosis in cancer patients.
Author contributions
W-QL: Writing – review & editing, Data curation, Software, Writing – original draft. J-YL: Data curation, Writing – original draft, Writing – review & editing. JL: Data curation, Conceptualization, Writing – original draft, Writing – review & editing. D-YL: Data curation, Software, Writing – original draft. QK: Writing – original draft, Software, Data curation.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by Talent plan of Taihu Lake in Wuxi (HB2020047), Research project of Wuxi Municipal Health Commission (M202304) and Clinical medical research project of the Affiliated Hospital of Jiangnan University (LCYJ202329).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
1. De Giglio A, Grandinetti V, Aprile M, Borelli G, Campus A, Croci Chiocchini AL, et al. Patterns of renal toxicity from the combination of pemetrexed and pembrolizumab for advanced nonsquamous non-small-cell lung cancer (NSCLC): A single-center experience. Lung Cancer. (2022) 174:91–6. doi: 10.1016/j.lungcan.2022.10.007
2. Perazella MA and Shirali AC. Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? Kidney Int. (2020) 97:62–74. doi: 10.1016/j.kint.2019.07.022
3. Kitchlu A, Reid J, Jeyakumar N, Dixon SN, Munoz AM, Silver SA, et al. Cancer risk and mortality in patients with kidney disease: A population-based cohort study. Am J Kidney Dis. (2022) 80:436–448.e1. doi: 10.1053/j.ajkd.2022.02.020
4. Lees JS, Elyan BMP, Herrmann SM, Lang NN, Jones RJ, and Mark PB. The 'other' big complication: how chronic kidney disease impacts on cancer risks and outcomes. Nephrol Dial Transplant. (2023) 38:1071–9. doi: 10.1093/ndt/gfac011
5. Tendulkar KK, Cope B, Dong J, Plumb TJ, Campbell WS, and Ganti AK. Risk of Malignancy in patients with chronic kidney disease. PloS One. (2022) 17:e0272910. doi: 10.1371/journal.pone.0272910
6. Park S, Lee S, Kim Y, Lee Y, Kang MW, Han K, et al. Risk of cancer in pre-dialysis chronic kidney disease: A nationwide population-based study with a matched control group. Kidney Res Clin Pract. (2019) 38:60–70. doi: 10.23876/j.krcp.18.0131
7. Butler AM, Olshan AF, Kshirsagar AV, Edwards JK, Nielsen ME, Wheeler SB, et al. Cancer incidence among US Medicare ESRD patients receiving hemodialysis, 1996–2009. Am J Kidney Dis. (2015) 65:763–72. doi: 10.1053/j.ajkd.2014.12.013
8. Kitchlu A, Silva V, Anand S, Kala J, Abudayyeh A, Inker LA, et al. Assessment of GFR in patients with cancer: A statement from the american society of onco-nephrology. Clin J Am Soc Nephrol. (2024) 19:1061–72. doi: 10.2215/cjn.0000000000000508
9. Strohbehn IA, Lee M, Seethapathy H, Chute D, Rahma O, Guidon A, et al. Safety and Efficacy of immune checkpoint inhibitors in patients on dialysis: A retrospective case series. Am J Kidney Dis. (2020) 76:299–302. doi: 10.1053/j.ajkd.2020.02.451
10. Tiu BC, Strohbehn IA, Zhao S, Ouyang T, Hanna P, Wang Q, et al. Safety of immune checkpoint inhibitors in patients with advanced chronic kidney disease: A retrospective. Cohort Study Oncologist. (2023) 28:e379–90. doi: 10.1093/oncolo/oyad001
11. Khan M, Arooj S, and Wang H. NK cell-based immune checkpoint inhibition. Front Immunol. (2020) 11:167. doi: 10.3389/fimmu.2020.00167
12. Hossen MM, Ma Y, Yin Z, Xia Y, Du J, Huang JY, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol. (2023), 14:1198365. doi: 10.3389/fimmu.2023.1198365
13. Sharpe AH and Freeman GJ. The B7-CD28 superfamily. Nat Rev Immunol. (2002) 2:116–26. doi: 10.1038/nri727
14. Munir AZ, Gutierrez A, Qin J, Lichtman AH, and Moslehi JJ. Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart. Nat Rev Cancer. (2024) 2024:540–53:24(8). doi: 10.1038/s41568-024-00715-5
15. Chen L and Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. (2013) 13:227–42. doi: 10.1038/nri3405
16. Ye Q, Liu J, and Xie K. B7 family proteins in cancer progression: immunological and non-immunological functions. J Cancer Treat diagnosis. (2019). doi: 10.29245/2578-2967/2019/4.1171
17. Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA, et al. Germline mutations in a G protein identify signaling cross-talk in T cells. Science. (2024) 385:eadd8947. doi: 10.1126/science.add8947
18. Liang Y, Zheng Y, Zeng Y, Hu C, Si Y, Fan X, et al. Immune checkpoint inhibitors in melanoma: mechanisms, immune cell interactions, and the tumour microenvironment. Front Immunol. (2025) 16:1691608. doi: 10.3389/fimmu.2025.1691608
19. Kwiatkowska E, Domański L, Dziedziejko V, Kajdy A, Stefańska K, and Kwiatkowski S. The mechanism of drug nephrotoxicity and the methods for preventing kidney damage. Int J Mol Sci. (2021) 22:6109. doi: 10.3390/ijms22116109
20. Wan G, Chen W, Khattab S, Roster K, Nguyen N, Yan B, et al. Multi-organ immune-related adverse events from immune checkpoint inhibitors and their downstream implications: a retrospective multicohort study. Lancet Oncol. (2024) 25:1053–69. doi: 10.1016/s1470-2045(24)00278-x
21. Longhitano E, Muscolino P, Lo Re C, Ferrara SA, Cernaro V, Gembillo G, et al. Immune checkpoint inhibitors and the kidney: A focus on diagnosis and management for personalised medicine. Cancers (Basel). (2023) 15:1891. doi: 10.3390/cancers15061891
22. Oleas D, Bolufer M, Agraz I, Felip E, Muñoz E, Gabaldón A, et al. Acute interstitial nephritis associated with immune checkpoint inhibitors: a single-centre experience. Clin Kidney J. (2021) 14:1364–70. doi: 10.1093/ckj/sfaa008
23. Kommer A, Stortz M, Kraus D, and Weinmann-Menke J. Immune checkpoint inhibitor-associated acute kidney injury: A single-center experience of biopsy-proven cases. J Clin Med. (2025) 14:3231. doi: 10.3390/jcm14093231
24. Esposito P, Bottini A, Lecini E, Cappadona F, Piaggio M, Macciò L, et al. Biopsy-proven acute tubulointerstitial nephritis in patients treated with immune checkpoint inhibitors: a pooled analysis of case reports. Front Oncol. (2023) 13:1221135. doi: 10.3389/fonc.2023.1221135
25. Gérard AO, Andreani M, Fresse A, Parassol N, Muzzone M, Pinel S, et al. Immune checkpoint inhibitors-induced nephropathy: a French national survey. Cancer Immunol Immunother. (2021) 70:3357–64. doi: 10.1007/s00262-021-02983-8
26. Cortazar FB, Marrone KA, Troxell ML, Ralto KM, Hoenig MP, Brahmer JR, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. (2016) 90:638–47. doi: 10.1016/j.kint.2016.04.008
27. Cortazar FB, Kibbelaar ZA, Glezerman IG, Abudayyeh A, Mamlouk O, Motwani SS, et al. Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: A multicenter study. J Am Soc Nephrol. (2020) 31:435–46. doi: 10.1681/asn.2019070676
28. Gallan AJ, Alexander E, Reid P, Kutuby F, Chang A, and Henriksen KJ. Renal vasculitis and pauci-immune glomerulonephritis associated with immune checkpoint inhibitors. Am J Kidney Dis. (2019) 74:853–6. doi: 10.1053/j.ajkd.2019.04.016
29. Lemoine M, Dilly B, Curie A, Hébert V, Laurent C, Hanoy M, et al. Ipilimumab-induced renal granulomatous arteritis: a case report. BMC Nephrol. (2019) 20:366. doi: 10.1186/s12882-019-1552-2
30. Park SD, Kim MS, Han MH, Kim YJ, Jung HY, Choi JY, et al. Renal sarcoidosis-like reaction induced by PD-1 inhibitor treatment in non-small cell lung cancer: A case report and literature review. Med (Kaunas). (2023) 59:991. doi: 10.3390/medicina59050991
31. Wang R, Das T, and Takou A. IgA nephropathy after pembrolizumab therapy for mesothelioma. BMJ Case Rep. (2020) 13:e237008. doi: 10.1136/bcr-2020-237008
32. Gupta S, Short SAP, Sise ME, Prosek JM, Madhavan SM, Soler MJ, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer. (2021) 9:e003467. doi: 10.1136/jitc-2021-003467
33. Li S, Zheng K, Xu Y, and Wang M. Immune checkpoint inhibitors related cystoureteritis:A case report and literature review. Zhongguo Fei Ai Za Zhi. (2023) 26:709–16. doi: 10.3779/j.issn.1009-3419.2023.106.17
34. He X, Liu F, Jin Y, Fu H, and Mao J. Glomerular diseases after immune checkpoint inhibitors use: What do We know so far? Ren Fail. (2022) 44:2046–55. doi: 10.1080/0886022x.2022.2147439
35. Manohar S, Ghamrawi R, Chengappa M, Goksu BNB, KottsChade L, Finnes H, et al. Acute interstitial nephritis and checkpoint inhibitor therapy: single center experience of management and drug rechallenge. Kidney 360. (2020) 1:16–24. doi: 10.34067/kid.0000152019
36. Knox A, Cloney T, Janssen H, Solomon BJ, Alexander M, Ruderman I, et al. Immune-related acute kidney injury in Australian non-small cell lung cancer patients: Real-world results. Lung Cancer. (2023) 184:107325. doi: 10.1016/j.lungcan.2023.107325
37. Gu Y, Yi L, Zou X, Guo L, Wu G, and Zhao J. Refractory hypokalemia and metabolic acidosis induced by undifferentiated connective tissue disease secondary to immune checkpoint inhibitors: a case report and literature review. Front Oncol. (2024) 14:1442605. doi: 10.3389/fonc.2024.1442605
38. Farid S, Latif H, Nilubol C, and Kim C. Immune checkpoint inhibitor-induced fanconi syndrome. Cureus. (2020) 12:e7686. doi: 10.7759/cureus.7686
39. Terashita M, Yazawa M, Murakami N, and Nishiyama A. Water and electrolyte abnormalities in novel pharmacological agents for kidney disease and cancer. Clin Exp Nephrol. (2025) 29:521–33. doi: 10.1007/s10157-025-02635-6
40. Seethapathy H, Herrmann SM, and Sise ME. Immune checkpoint inhibitors and kidney toxicity: advances in diagnosis and management. Kidney Med. (2021) 3:1074–81. doi: 10.1016/j.xkme.2021.08.008
41. Guven DC, Ozbek DA, Sahin TK, Kavgaci G, Aksun MS, Erul E, et al. The incidence and risk factors for acute kidney injury in patients treated with immune checkpoint inhibitors. Anticancer Drugs. (2023) 34:783–90. doi: 10.1097/cad.0000000000001463
42. Liu C, Wei W, Yang L, Li J, Yi C, Pu Y, et al. Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol. (2023) 14:1173952. doi: 10.3389/fimmu.2023.1173952
43. Liu K, Qin Z, Ge Y, Bian A, Xu X, Wu B, et al. Acute kidney injury in advanced lung cancer patients treated with PD-1 inhibitors: a single center observational study. J Cancer Res Clin Oncol. (2023) 149:5061–70. doi: 10.1007/s00432-022-04437-9
44. Mohan A, Krisanapan P, Tangpanithandee S, Thongprayoon C, Kanduri SR, Cheungpasitporn W, et al. Association of proton pump inhibitor use and immune checkpoint inhibitor-mediated acute kidney injury: A meta-analysis and a review of related outcomes. Am J Nephrol. (2024) 55:439–49. doi: 10.1159/000538274
45. Hammond S, Olsson-Brown A, Gardner J, Thomson P, Ali SE, Jolly C, et al. T cell mediated hypersensitivity to previously tolerated iodinated contrast media precipitated by introduction of atezolizumab. J Immunother Cancer. (2021) 9:e002521. doi: 10.1136/jitc-2021-002521
46. Grabska S, Grabski H, Makunts T, and Abagyan R. Co-occurring infections in cancer patients treated with checkpoint inhibitors significantly increase the risk of immune-related adverse events. Cancers (Basel). (2024) 16:2820. doi: 10.3390/cancers16162820
47. Chen P, Zhu J, Xu Y, Huang Q, Su J, Gao Z, et al. Risk factors of immune checkpoint inhibitor-associated acute kidney injury: evidence from clinical studies and FDA pharmacovigilance database. BMC Nephrol. (2023) 24:107. doi: 10.1186/s12882-023-03171-9
48. Khan S, Malladi VS, von Itzstein MS, Mu-Mosley H, Fattah FJ, Liu Y, et al. Innate and adaptive immune features associated with immune-related adverse events. J Immunother Cancer. (2025) 13:e012414. doi: 10.1136/jitc-2025-012414
49. Adam BA, Murakami N, Reid G, Du K, Jasim R, Boils CL, et al. Gene expression profiling in kidney transplants with immune checkpoint inhibitor-associated adverse events. Clin J Am Soc Nephrol. (2021) 16:1376–86. doi: 10.2215/cjn.00920121
50. Liu S, Lu P, Yang B, Yang Y, Zhou H, and Yang M. Single-cell RNA sequencing analysis of peripheral blood mononuclear cells in PD-1-induced renal toxicity in patients with lung cancer. BMC Nephrol. (2024) 25:307. doi: 10.1186/s12882-024-03754-0
51. Ma Y, Chen Y, Yao Q, Wang Y, Ouyang N, Han F, et al. Resident macrophage-orchestrated immune and fibroblast interactions in immune checkpoint inhibitor-associated nephrotoxicity. Adv Sci (Weinh). (2025) 12(42):e05445. doi: 10.1002/advs.202505445
52. Long JP, Singh S, Dong Y, Yee C, and Lin JS. Urine proteomics defines an immune checkpoint-associated nephritis signature. J Immunother Cancer. (2025) 13:e010680. doi: 10.1136/jitc-2024-010680
53. Francisco LM, Sage PT, and Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev. (2010) 236:219–42. doi: 10.1111/j.1600-065X.2010.00923.x
54. Moturi K, Sharma H, and Hashemi-Sadraei N. Nephrotoxicity in the age of immune checkpoint inhibitors: mechanisms, diagnosis, and management. Int J Mol Sci. (2023) 25:414. doi: 10.3390/ijms25010414
55. Zehn D and Bevan MJ. T. cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity. (2006) 25:261–70. doi: 10.1016/j.immuni.2006.06.009
56. Richards DM, Kyewski B, and Feuerer M. Re-examining the nature and function of self-reactive T cells. Trends Immunol. (2016) 37:114–25. doi: 10.1016/j.it.2015.12.005
57. Izzedine H, Gueutin V, Gharbi C, Mateus C, Robert C, Routier E, et al. Kidney injuries related to ipilimumab. Invest New Drugs. (2014) 32:769–73. doi: 10.1007/s10637-014-0092-7
58. Benfaremo D, Manfredi L, Luchetti MM, and Gabrielli A. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: A review of the literature. Curr Drug Saf. (2018) 13:150–64. doi: 10.2174/1574886313666180508122332
59. Franzin R, Netti GS, Spadaccino F, Porta C, Gesualdo L, Stallone G, et al. The use of immune checkpoint inhibitors in oncology and the occurrence of AKI: where do we stand? Front Immunol. (2020) 11:574271. doi: 10.3389/fimmu.2020.574271
60. Ding H, Wu X, and Gao W. PD-L1 is expressed by human renal tubular epithelial cells and suppresses T cell cytokine synthesis. Clin Immunol. (2005) 115:184–91. doi: 10.1016/j.clim.2005.01.005
61. Catalano M, Roviello G, Galli IC, Santi R, and Nesi G. Immune checkpoint inhibitor induced nephrotoxicity: An ongoing challenge. Front Med (Lausanne). (2022) 9:1014257. doi: 10.3389/fmed.2022.1014257
62. Karimzadeh I, Barreto EF, Kellum JA, Awdishu L, Murray PT, Ostermann M, et al. Moving toward a contemporary classification of drug-induced kidney disease. Crit Care. (2023) 27:435. doi: 10.1186/s13054-023-04720-2
63. Gupta S, Mistry K, Alikhan FM, Mejia SM, Sadarangani S, Cao A, et al. Urinary C-X-C-motif ligand 9 (CXCL9) in immune checkpoint inhibitor-associated acute interstitial nephritis. Kidney Int. (2025) 108(3):491–6. doi: 10.1016/j.kint.2025.05.029
64. Moledina DG, Wilson FP, Pober JS, Perazella MA, Singh N, Luciano RL, et al. TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight. (2019) 4:e127456. doi: 10.1172/jci.insight.127456
65. Farooqui N, Zaidi M, Vaughan L, McKee TD, Ahsan E, Pavelko KD, et al. Cytokines and immune cell phenotype in acute kidney injury associated with immune checkpoint inhibitors. Kidney Int Rep. (2023) 8:628–41. doi: 10.1016/j.ekir.2022.11.020
66. Martinez Valenzuela L, Draibe J, Bestard O, Fulladosa X, Gómez-Preciado F, Antón P, et al. Urinary cytokines reflect renal inflammation in acute tubulointerstitial nephritis: A multiplex bead-based assay assessment. J Clin Med. (2021) 10:2986. doi: 10.3390/jcm10132986
67. Martinez Valenzuela L, Gómez-Preciado F, Guiteras J, Antón Pampols P, Gomà M, Fulladosa X, et al. Immune checkpoint inhibitors induce acute interstitial nephritis in mice with increased urinary MCP1 and PD-1 glomerular expression. J Transl Med. (2024) 22:421. doi: 10.1186/s12967-024-05177-9
68. Sise ME, Wang Q, Seethapathy H, Moreno D, Harden D, Smith RN, et al. Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis. J Immunother Cancer. (2023) 11:e006222. doi: 10.1136/jitc-2022-006222
69. Perier T, Renaudineau Y, Pellegrini J, Colombat M, Ramirez AA, Guy P, et al. CD163 detection in immune check-point inhibitors-related acute interstitial nephritis. Clinical Kidney Journal. (2025) 18(3):sfaf009. doi: 10.1093/ckj/sfaf009
70. Sun PP, Zhou XJ, Su JQ, Wang C, Yu XJ, Su T, et al. Urine macrophages reflect kidney macrophage content during acute tubular interstitial and glomerular injury. Clin Immunol. (2019) 205:65–74. doi: 10.1016/j.clim.2019.06.005
71. Kim MG, Lim K, Lee YJ, Yang J, Oh SW, Cho WY, et al. M2 macrophages predict worse long-term outcomes in human acute tubular necrosis. Sci Rep. (2020) 10:2122. doi: 10.1038/s41598-020-58725-w
72. Singh S, Clemente LC, Parra ER, Tchakarov A, Yang C, Li Y, et al. Urinary T cells are detected in patients with immune checkpoint inhibitor-associated immune nephritis that are clonotypically identical to kidney T cell infiltrates. Oncoimmunology. (2022) 11:2124678. doi: 10.1080/2162402x.2022.2124678
73. Gomez-Preciado F, Martinez-Valenzuela L, Anton-Pampols P, Fulladosa X, Tena MG, Gomà M, et al. Urinary soluble PD-1 as a biomarker of checkpoint inhibitor-induced acute tubulointerstitial nephritis. Clin Kidney J. (2024) 17:sfae200. doi: 10.1093/ckj/sfae200
74. Isik B, Alexander MP, Manohar S, Vaughan L, KottsChade L, Markovic S, et al. Biomarkers, clinical features, and rechallenge for immune checkpoint inhibitor renal immune-related adverse events. Kidney Int Rep. (2021) 6:1022–31. doi: 10.1016/j.ekir.2021.01.013
75. Seethapathy H, Mistry K, and Sise ME. Immunological mechanisms underlying clinical phenotypes and noninvasive diagnosis of immune checkpoint inhibitor-induced kidney disease. Immunol Rev. (2023) 318:61–9. doi: 10.1111/imr.13243
76. von Euw E, Chodon T, Attar N, Jalil J, Koya RC, Comin-Anduix B, et al. CTLA4 blockade increases Th17 cells in patients with metastatic melanoma. J Transl Med. (2009) 7:35. doi: 10.1186/1479-5876-7-35
77. Bermejo S, Bolufer M, Riveiro-Barciela M, and Soler MJ. Immunotherapy and the spectrum of kidney disease: should we individualize the treatment? Front Med (Lausanne). (2022) 9:906565. doi: 10.3389/fmed.2022.906565
78. Barbir EB, Kitchlu A, and Herrmann SM. Immune checkpoint inhibitor-associated nephritis-treatment standard. Nephrol Dial Transplant. (2024) 39:1785–98. doi: 10.1093/ndt/gfae184
79. Ferreira CA, Heidari P, Ataeinia B, Sinevici N, Sise ME, Colvin RB, et al. Non-invasive detection of immunotherapy-induced adverse events. Clin Cancer Res. (2021) 27:5353–64. doi: 10.1158/1078-0432.Ccr-20-4641
80. Gupta S, Green-Lingren O, Bhimaniya S, Krokhmal A, Jacene H, Ostermann M, et al. F18-FDG PET imaging as a diagnostic tool for immune checkpoint inhibitor-associated acute kidney injury. J Clin Invest. (2024) 134:e182275. doi: 10.1172/jci182275
81. Seethapathy H, Herrmann SM, and Rashidi A. Immune checkpoint inhibitor-associated AKI: debates in diagnosis, management, and rechallenge. Semin Nephrol. (2022) 42:151346. doi: 10.1016/j.semnephrol.2023.151346
82. Wang Y, Xiong C, Yu W, Zhou M, Shugg T, Hsu FC, et al. PCCA variant rs16957301 is a novel AKI risk genotype-specific for patients who receive ICI treatment: Real-world evidence from all of us cohort. Eur J Cancer. (2024) 213:115114. doi: 10.1016/j.ejca.2024.115114
83. Monson KR, Ferguson R, Handzlik JE, Xiong J, Dagayev S, Morales L, et al. Tyrosine protein kinase SYK-related gene signature in baseline immune cells associated with adjuvant immunotherapy-induced immune-related adverse events in melanoma. Clin Cancer Res. (2024) 30:4412–23. doi: 10.1158/1078-0432.Ccr-24-0900
84. Kobayashi M, Numakura K, Hatakeyama S, Muto Y, Sekine Y, Sasagawa H, et al. Severe immune-related adverse events in patients treated with nivolumab for metastatic renal cell carcinoma are associated with PDCD1 polymorphism. Genes (Basel). (2022) 13:1204. doi: 10.3390/genes13071204
85. Lumlertgul N, Vassallo P, Tydeman F, Lewis N, Hobill A, Weerapolchai K, et al. Acute kidney injury in patients receiving immune checkpoint inhibitors: a retrospective real-world study. Eur J Cancer. (2023) 191:112967. doi: 10.1016/j.ejca.2023.112967
86. Abudayyeh A, Suo L, Lin H, Mamlouk O, Abdel-Wahab N, and Tchakarov A. Pathologic predictors of response to treatment of immune checkpoint inhibitor-induced kidney injury. Cancers (Basel). (2022) 14:5267. doi: 10.3390/cancers14215267
87. Gupta S, Garcia-Carro C, Prosek JM, Glezerman I, Herrmann SM, Garcia P, et al. Shorter versus longer corticosteroid duration and recurrent immune checkpoint inhibitor-associated AKI. J Immunother Cancer. (2022) 10:e005646. doi: 10.1136/jitc-2022-005646
88. Elghawy O, Patel R, Barsouk A, Puthumana J, Xu J, Sussman J, et al. Diagnosis, management, and outcomes of immune checkpoint inhibitor induced acute interstitial nephritis: A single-center experience. J Oncol Pharm Pract. (2025) 31:641–8. doi: 10.1177/10781552241252627
89. Zhou P, Liu B, Shen N, Fan X, Lu S, Kong Z, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors: a single-center retrospective study. Ren Fail. (2024) 46:2326186. doi: 10.1080/0886022x.2024.2326186
90. Lin JS, Mamlouk O, Selamet U, Tchakarov A, Glass WF, Sheth RA, et al. Infliximab for the treatment of patients with checkpoint inhibitor-associated acute tubular interstitial nephritis. Oncoimmunology. (2021) 10:1877415. doi: 10.1080/2162402x.2021.1877415
91. Mamlouk O, Lin JS, Abdelrahim M, Tchakarov AS, Glass WF, Selamet U, et al. Checkpoint inhibitor-related renal vasculitis and use of rituximab. J Immunother Cancer. (2020) 8:e000750. doi: 10.1136/jitc-2020-000750
92. Rassner M, Baur R, Wäsch R, Schiffer M, Schneider J, Mackensen A, et al. Two cases of carfilzomib-induced thrombotic microangiopathy successfully treated with Eculizumab in multiple myeloma. BMC Nephrol. (2021) 22:32. doi: 10.1186/s12882-020-02226-5
93. Shivaraj K, Tchakarov A, Dong Y, and Lin JS. Tofacitinib for the treatment of refractory immune checkpoint inhibitor-associated immune nephritis. Clin Kidney J. (2024) 17:sfae127. doi: 10.1093/ckj/sfae127
94. Herrmann SM, Abudayyeh A, Gupta S, Gudsoorkar P, Klomjit N, Motwani SS, et al. Diagnosis and management of immune checkpoint inhibitor-associated nephrotoxicity: a position statement from the American Society of Onco-nephrology. Kidney Int. (2025) 107:21–32. doi: 10.1016/j.kint.2024.09.017
95. Curkovic NB, Irlmeier R, Bai X, Cui C, Ye F, Burnette HR, et al. Impact of steroid dose and timing on efficacy of combination PD-1/CTLA-4 blockade. Oncoimmunology. (2025) 14:2494433. doi: 10.1080/2162402x.2025.2494433
96. Luo J, Beattie JA, Fuentes P, Rizvi H, Egger JV, Kern JA, et al. Beyond steroids: immunosuppressants in steroid-refractory or resistant immune-related adverse events. J Thorac Oncol. (2021) 16:1759–64. doi: 10.1016/j.jtho.2021.06.024
97. Barbir EB, Mohan A, Koirala P, Gutierrez LE, Giesen CD, Lieske JC, et al. Biomarker-guided infliximab therapy for immune checkpoint inhibitor-induced acute interstitial nephritis. Nephrol Dial Transplant. (2025) 40:602–4. doi: 10.1093/ndt/gfae257
98. Henderson Berg MH, Del Rincón SV, and Miller WH. Potential therapies for immune-related adverse events associated with immune checkpoint inhibition: from monoclonal antibodies to kinase inhibition. J Immunother Cancer. (2022) 10:e003551. doi: 10.1136/jitc-2021-003551
99. Zhao Q, Zhang J, Xu L, Yang H, Liang N, Zhang L, et al. Safety and efficacy of the rechallenge of immune checkpoint inhibitors after immune-related adverse events in patients with cancer: A systemic review and meta-analysis. Front Immunol. (2021) 12:730320. doi: 10.3389/fimmu.2021.730320
100. Liu SJ, Yan LJ, Wang HC, Ding ZN, Liu H, Zhang X, et al. Safety, efficacy, and survival outcomes of immune checkpoint inhibitors rechallenge in patients with cancer: a systematic review and meta-analysis. Oncologist. (2024) 29:e1425–34. doi: 10.1093/oncolo/oyae134
101. Xu S, Shukuya T, Tamura J, Shimamura S, Kurokawa K, Miura K, et al. Heterogeneous outcomes of immune checkpoint inhibitor rechallenge in patients with NSCLC: A systematic review and meta-analysis. JTO Clin Res Rep. (2022) 3:100309. doi: 10.1016/j.jtocrr.2022.100309
102. Kitchlu A, Jhaveri KD, Sprangers B, Yanagita M, and Wanchoo R. Immune checkpoint inhibitor use in patients with end-stage kidney disease: an analysis of reported cases and literature review. Clin Kidney J. (2021) 14:2012–22. doi: 10.1093/ckj/sfab090
103. Hoffman-Censits J, Pal S, Kaiser C, Ding B, and Bellmunt J. Atezolizumab in patients with renal insufficiency and mixed variant histology: analyses from an expanded access program in platinum-treated locally advanced or metastatic urothelial carcinoma. J Immunother Cancer. (2020) 8:e000419. doi: 10.1136/jitc-2019-000419
104. Seydel F, Delecluse S, Zeier M, Holland-Letz T, Haag GM, Berger AK, et al. Efficacy and safety of checkpoint inhibitor treatment in patients with advanced renal or urothelial cell carcinoma and concomitant chronic kidney disease: A retrospective cohort study. Cancers (Basel). (2021) 13:1623. doi: 10.3390/cancers13071623
105. Yun JW, Kwon J, and Lim T. Long-term response of pembrolizumab in a patient with metastatic squamous non-small cell lung cancer on hemodialysis: case report and review of the literature. Med (Kaunas). (2023) 59:325. doi: 10.3390/medicina59020325
106. Kobari Y, Yoshida K, Iizuka J, Kondo T, Ishida H, Tanabe K, et al. Three cases of nivolumab plus ipilimumab therapy in haemodialysis patients with metastatic renal cell carcinoma. In Vivo. (2021) 35:3585–9. doi: 10.21873/invivo.12663
107. Sise ME, Seethapathy H, and Reynolds KL. Diagnosis and management of immune checkpoint inhibitor-associated renal toxicity: illustrative case and review. Oncologist. (2019) 24:735–42. doi: 10.1634/theoncologist.2018-0764
108. Engels EA, Pfeiffer RM, Fraumeni JF Jr., Kasiske BL, Israni AK, Snyder JJ, et al. Spectrum of cancer risk among US solid organ transplant recipients. Jama. (2011) 306:1891–901. doi: 10.1001/jama.2011.1592
109. Al-Adra D, Al-Qaoud T, Fowler K, and Wong G. De novo Malignancies after kidney transplantation. Clin J Am Soc Nephrol. (2022) 17:434–43. doi: 10.2215/cjn.14570920
110. Nimmo A, Elyan B, Lakey J, Marjoribanks S, Methven S, Morrison D, et al. Increased cancer risk in kidney transplant patients in Scotland: a national registry linkage study. Br J Cancer. (2025) 133:555–63. doi: 10.1038/s41416-025-03086-2
111. Yanik EL, Clarke CA, Snyder JJ, Pfeiffer RM, and Engels EA. Variation in Cancer Incidence among Patients with ESRD during Kidney Function and Nonfunction Intervals. J Am Soc Nephrol. (2016) 27:1495–504. doi: 10.1681/asn.2015040373
112. Leonforte F, Mistretta A, Nicosia V, Micalizzi MC, Londrigo D, Giambra MM, et al. Epidemiological overview of colorectal cancer in kidney transplant recipients: A systematic review. Cancers (Basel). (2025) 17:3352. doi: 10.3390/cancers17203352
113. Blosser CD, Haber G, and Engels EA. Changes in cancer incidence and outcomes among kidney transplant recipients in the United States over a thirty-year period. Kidney Int. (2021) 99:1430–8. doi: 10.1016/j.kint.2020.10.018
114. Merzkani M, Attieh RM, Jhaveri KD, and Murakami N. Immunotherapy and cellular therapies for cancers in kidney transplant patients. Am J Nephrol. (2025), 1–14. doi: 10.1159/000544826
115. Legris T, Sallée M, Charmetant X, Thaunat O, Matignon M, Joher N, et al. Immune checkpoint inhibitors in kidney transplant recipients: A french multicenter retrospective cohort study. Transplant Direct. (2025) 11:e1851. doi: 10.1097/txd.0000000000001851
116. Murakami N, Mulvaney P, Danesh M, Abudayyeh A, Diab A, Abdel-Wahab N, et al. A multi-center study on safety and efficacy of immune checkpoint inhibitors in cancer patients with kidney transplant. Kidney Int. (2021) 100:196–205. doi: 10.1016/j.kint.2020.12.015
117. Abdel-Wahab N, Safa H, Abudayyeh A, Johnson DH, Trinh VA, Zobniw CM, et al. Checkpoint inhibitor therapy for cancer in solid organ transplantation recipients: an institutional experience and a systematic review of the literature. J Immunother Cancer. (2019) 7:106. doi: 10.1186/s40425-019-0585-1
118. Kumar V, Shinagare AB, Rennke HG, Ghai S, Lorch JH, Ott PA, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: A case series and systematic review of literature. Oncologist. (2020) 25:505–14. doi: 10.1634/theoncologist.2019-0659
119. Saleem N, Wang J, Rejuso A, Teixeira-Pinto A, Stephens JH, Wilson A, et al. Outcomes of solid organ transplant recipients with advanced cancers receiving immune checkpoint inhibitors: A systematic review and individual participant data meta-analysis. JAMA Oncol. (2025) 11:1150–9. doi: 10.1001/jamaoncol.2025.2374
120. Khan MA, Mehmood M, El Azzazi H, Shaikh S, Bhasin-Chhabra B, Gudsoorkar P, et al. Immune checkpoint inhibitors and allograft rejection risk: emerging evidence regarding their use in kidney transplant recipients. J Clin Med. (2025) 14:5152. doi: 10.3390/jcm14145152
121. Loupy A, Certain A, Tangprasertchai NS, Racapé M, Ursule-Dufait C, Benbadi K, et al. Evaluation of a decentralized donor-derived cell-free DNA assay for kidney allograft rejection monitoring. Transpl Int. (2024) 37:13919. doi: 10.3389/ti.2024.13919
122. Rabant M, Amrouche L, Lebreton X, Aulagnon F, Benon A, Sauvaget V, et al. Urinary C-X-C motif chemokine 10 independently improves the noninvasive diagnosis of antibody-mediated kidney allograft rejection. J Am Soc Nephrol. (2015) 26:2840–51. doi: 10.1681/asn.2014080797
123. Jacquemont L, Tilly G, Yap M, Doan-Ngoc TM, Danger R, Guérif P, et al. Terminally differentiated effector memory CD8(+) T cells identify kidney transplant recipients at high risk of graft failure. J Am Soc Nephrol. (2020) 31:876–91. doi: 10.1681/asn.2019080847
124. Chesneau M, Michel L, Dugast E, Chenouard A, Baron D, Pallier A, et al. Tolerant kidney transplant patients produce B cells with regulatory properties. J Am Soc Nephrol. (2015) 26:2588–98. doi: 10.1681/asn.2014040404
125. Tsung I, Worden FP, and Fontana RJ. A pilot study of checkpoint inhibitors in solid organ transplant recipients with metastatic cutaneous squamous cell carcinoma. Oncologist. (2021) 26:133–8. doi: 10.1002/onco.13539
126. Danesh MJ, Mulvaney PM, Murakami N, Riella LV, Silk AW, Hanna GJ, et al. Impact of corticosteroids on allograft protection in renal transplant patients receiving anti-PD-1 immunotherapy. Cancer Immunol Immunother. (2020) 69:1937–41. doi: 10.1007/s00262-020-02644-2
127. Bolufer M, Soler J, Molina M, Taco O, Vila A, and Macía M. Immunotherapy for cancer in kidney transplant patients: A difficult balance between risks and benefits. Transpl Int. (2024) 37:13204. doi: 10.3389/ti.2024.13204
128. Huang E, Adjei M, Peng A, Najjar R, Shoji J, Chandran S, et al. Tocilizumab treatment for microvascular inflammation and chronic active antibody-mediated rejection in kidney transplantation. Transplant Direct. (2025) 11:e1867. doi: 10.1097/txd.0000000000001867
129. Noble J, Comai G, Corredetti V, Laamech R, Dard C, Jouve T, et al. Tocilizumab-based treatment of microvascular inflammation in kidney transplant recipients: A retrospective study. Transpl Int. (2025) 38:14502. doi: 10.3389/ti.2025.14502
130. Moon S, Jung M, Go S, Hong J, Sohn HS, Kim C, et al. Engineered nanoparticles for enhanced antitumoral synergy between macrophages and T cells in the tumor microenvironment. Adv Mater. (2024) 36:e2410340. doi: 10.1002/adma.202410340
131. Liu P, Guo J, Xie Z, Pan Y, Wei B, Peng Y, et al. Co-delivery of aPD-L1 and CD73 inhibitor using calcium phosphate nanoparticles for enhanced melanoma immunotherapy with reduced toxicity. Adv Sci (Weinh). (2025) 12:e2410545. doi: 10.1002/advs.202410545
132. Yu R, Zhu B, and Chen D. Type I interferon-mediated tumor immunity and its role in immunotherapy. Cell Mol Life Sci. (2022) 79:191. doi: 10.1007/s00018-022-04219-z
133. Hu M, Zhou M, Bao X, Pan D, Jiao M, Liu X, et al. ATM inhibition enhances cancer immunotherapy by promoting mtDNA leakage and cGAS/STING activation. J Clin Invest. (2021) 131:e139333. doi: 10.1172/jci139333
134. Zhong N, Zu Z, Lu Y, Sha X, Li Y, Liu Y, et al. Mitochondria-targeted manganese-based mesoporous silica nanoplatforms trigger cGAS-STING activation and sensitize anti PD-L1 therapy in triple-negative breast cancer. Acta Biomater. (2025) 199:374–86. doi: 10.1016/j.actbio.2025.04.040
135. Li L, Liu F, Feng C, Chen Z, Zhang N, and Mao J. Role of mitochondrial dysfunction in kidney disease: Insights from the cGAS-STING signaling pathway. Chin Med J (Engl). (2024) 137:1044–53. doi: 10.1097/cm9.0000000000003022
136. Zhu H, Wang J, Miao J, Shen M, Wang H, Huang X, et al. SNORD3A regulates STING transcription to promote ferroptosis in acute kidney injury. Adv Sci (Weinh). (2024) 11:e2400305. doi: 10.1002/advs.202400305
137. Xu Z, Yang X, Lu X, Su D, Wang Y, Wu H, et al. PD-L1 antibody-modified plant-derived nanovesicles carrying a STING agonist for the combinational immunotherapy of melanoma. Biomaterials. (2025) 322:123396. doi: 10.1016/j.biomaterials.2025.123396
138. Yen YT, Zhang Z, Chen A, Qiu Y, Liu Q, Wang Q, et al. Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and elicit robust therapeutic efficacy. J Nanobiotechnol. (2025) 23:124. doi: 10.1186/s12951-025-03129-z
139. Li Y, Liu J, Weichselbaum RR, and Lin W. Mitochondria-targeted multifunctional nanoparticles combine cuproptosis and programmed cell death-1 downregulation for cancer immunotherapy. Adv Sci (Weinh). (2024) 11:e2403520. doi: 10.1002/advs.202403520
140. Rebeck ON, Wallace MJ, Prusa J, Ning J, Evbuomwan EM, Rengarajan S, et al. A yeast-based oral therapeutic delivers immune checkpoint inhibitors to reduce intestinal tumor burden. Cell Chem Biol. (2025) 32:98–110.e7. doi: 10.1016/j.chembiol.2024.10.013
Keywords: immune checkpoint inhibitors, renal immune-related adverse events, chronic kidney disease, mechanism, biomarkers, treatment
Citation: Lv W-Q, Lu J-Y, Li J, Lv D-Y and Ke Q (2026) Urgent considerations on renal immune-related adverse events in oncology practice. Front. Immunol. 16:1714090. doi: 10.3389/fimmu.2025.1714090
Received: 27 September 2025; Accepted: 31 December 2025; Revised: 18 December 2025;
Published: 10 February 2026.
Edited by:
Cleber Machado-Souza, Pelé Pequeno Príncipe Research Institute, BrazilReviewed by:
Wim Lemahieu, Imelda Hospital, BelgiumFariba Mahmoodpoo, Tabriz University of Medical Sciences, Iran
Copyright © 2026 Lv, Lu, Li, Lv and Ke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jun Li, bGlqdW5tZWRAMTYzLmNvbQ==