<h4>Background</h4>Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are complicated by immune-related adverse events, including acute kidney injury (AKI). As clinical experience matures and treatment durations lengthen, initial estimates of ICI-AKI incidence and the perceived risks of resuming therapy may become outdated.<h4>Objective</h4>We aimed to provide a compelling, contemporary synthesis of the epidemiology, management outcomes, and specifically the safety profile of ICI rechallenge following ICI-AKI, integrating recent large-scale, real-world evidence accumulated through 2025.<h4>Methods</h4>We conducted a cumulative systematic review and meta-analysis (PRISMA 2020) searching PubMed/MEDLINE, Embase, The Cochrane Library (CENTRAL), Web of Science, and Scopus databases from inception through December 1, 2025. We included clinical studies reporting incidence, renal recovery following corticosteroid treatment, or recurrence rates upon ICI rechallenge. Data were pooled using random-effects models, with pre-specified subgroup analyses stratified by age to identify susceptible populations.<h4>Results</h4>A total of 60,799 patients from 21 studies were included. The pooled incidence of ICI-AKI was 2.61% (95% CI: 1.95, 3.28). While corticosteroid treatment showed a potential association with renal recovery (OR, 0.55; 95% CI: 0.06, 1.04; p = 0.03). Notably, the pooled recurrence rate of AKI upon ICI rechallenge decreased to 14.07% (95% CI: 10.26, 17.89; p = 0.00). Subgroup analysis revealed an age paradox: patients <65 years demonstrated a higher incidence but a significantly lower risk of recurrence upon rechallenge compared to older patients (10.6% vs 19.1%, respectively). Meta-regression analyses indicated that higher baseline serum creatinine was independently associated with an increased risk of ICI-AKI, with each 0.1 mg/dL increment conferring a substantial rise in effect size (coefficient 0.42, 95% CI 0.15-0.69; P < 0.01).<h4>Conclusions< We included clinical studies reporting incidence, renal recovery following corticosteroid treatment, or recurrence rates upon ICI rechallenge. Data were pooled using random-effects models, with pre-specified subgroup analyses stratified by age to identify susceptible populations. Results A total of 60,799 patients from 21 studies were included. The pooled incidence of ICI-AKI was 2.61% (95% CI: 1.95, 3.28). While corticosteroid treatment showed a potential association with renal recovery (OR, 0.55; 95% CI: 0.06, 1.04; p = 0.03). Notably, the pooled recurrence rate of AKI upon ICI rechallenge decreased to 14.07% (95% CI: 10.26, 17.89; p = 0.00). Subgroup analysis revealed an age paradox: patients <65 years demonstrated a higher incidence but a significantly lower risk of recurrence upon rechallenge compared to older patients (10.6% vs 19.1%, respectively). Meta-regression analyses indicated that higher baseline serum creatinine was independently associated with an increased risk of ICI-AKI, with each 0.1 mg/dL increment conferring a substantial rise in effect size (coefficient 0.42, 95% CI 0.15–0.69; P < 0.01). Conclusions The landscape of ICI-related nephrotoxicity is evolving. While early clinical trials reported a relatively low incidence of ICI-associated acute kidney injury (ICI-AKI) ranging from 2% to 3%, subsequent real-world cohorts and biopsy series have unmasked a more pervasive burden, with incidence rates climbing significantly higher in unselected populations, particularly those receiving combination immunotherapy ( 6 – 8 ). The clinical conundrum of ICI-AKI is profound: it necessitates the interruption of potentially life-saving cancer therapy and the initiation of immunosuppression, typically corticosteroids, thereby placing the patient at a precarious intersection of tumor progression risk and renal failure ( 9 ). This model assumes that the true effect size varies between studies, providing a more conservative and generalizable estimate than a fixed-effect model5. 2.7.4. Heterogeneity analysis Heterogeneity was quantified using the I 2 statistic and assessed for significance using the Cochran Q test. I 2 values of 25%, 50%, and 75% were interpreted as low, moderate, and high heterogeneity, respectively. 2.7.5. Subgroup analysis and meta-regression To investigate sources of heterogeneity and test our hypothesis regarding age-related risks, we performed pre-specified Subgroup Analyses stratified by: 1)Age: Elderly (≥ 65 years) vs. Non-elderly (< 65 years). 2)Study Design: Registry/Database studies vs. Primary outcome: incidence of ICI-AKI 3.3.1. Global incidence A forest plot presenting data from 12 studies, published between 2019 and 2025, demonstrates individual incidence rates ranging from a low of 0.79% [0.38, 1.21] to a high of 8.47% [3.45, 13.50]. The overall pooled incidence, calculated using a random-effects model, was 2.61% (95% CI: 1.95, 3.28), with notable heterogeneity across the included studies (I² = 93.09%, p = 0.00) ( Figure 2 ). Figure 2 Forest plot illustrating the incidence of AKI following treatment of ICI among patients with cancer. This forest plot presents a random-effects meta-analysis of five studies published between 2016 and 2025, evaluating the efficacy of treatment versus control management on AKI recovery outcomes. The analysis reveals low heterogeneity among the included studies (I 2 = 16.50%, p = 0.49) ( Figure 4 ). Meta-regression analysis In meta-regression analyses exploring sources of heterogeneity in the incidence of immune checkpoint inhibitor–associated acute kidney injury (ICI-AKI) ( Table 3 ), baseline renal function emerged as the only significant modifying factor. Specifically, higher baseline serum creatinine was independently associated with an increased risk of ICI-AKI, with each 0.1 mg/dL increment conferring a substantial rise in effect size (coefficient 0.42, 95% CI 0.15–0.69; P < 0.01), underscoring the critical role of pre-existing renal vulnerability.

addition to their corticosteroid activity, some corticosteroids may have some progestogenic activity and may produce sex-related side effects. Patients' response Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, and also their synthetic analogues. The two main classes of corticosteroids – glucocorticoids and mineralocorticoids – are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, Topical formulations are also available for the skin, eyes (uveitis), lungs (asthma), nose (rhinitis), and bowels. Corticosteroids are also used supportively to prevent nausea, often in combination with 5-HT3 antagonists (e.g., ondansetron). Typical undesired effects of glucocorticoids present quite uniformly as drug-induced Cushing's syndrome. Typical mineralocorticoid side-effects are hypertension (abnormally high blood pressure), steroid induced diabetes mellitus, psychosis, poor sleep, hypokalemia (low potassium levels in the blood), hypernatremia (high sodium levels in the blood) without causing peripheral edema, metabolic alkalosis and connective tissue weakness. Wound healing or ulcer formation may be inhibited by the immunosuppressive effects. A variety of steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, to eye drops (Tobradex), to prednisone have been implicated in the development of central serous retinopathy (CSR). Corticosteroids have been widely used in treating people with traumatic brain injury. A systematic review identified 20 randomised controlled trials and included 12,303 participants, then compared patients who received corticosteroids with patients who received no treatment. The authors recommended people with traumatic head injury should not be routinely treated with corticosteroids. Severe amoebic colitis: Fulminant amoebic colitis is associated with high case fatality and can occur in patients infected with the parasite Entamoeba histolytica after exposure to corticosteroid medications. Neuropsychiatric: steroid psychosis, and anxiety, depression. Therapeutic doses may cause a feeling of artificial well-being known as "steroid euphoria". Rare case reports of corticosteroid misuse, addiction, and dependence due to euphoria exist. The neuropsychiatric effects are partly mediated by sensitization of the body to the actions of adrenaline. Therapeutically, the bulk of corticosteroid dose is given in the morning to mimic the body's diurnal rhythm; if given at night, the feeling of being energized will interfere with sleep. An extensive review is provided by Flores and Gumina. Cardiovascular:…