Immune checkpoint inhibitor-associated acute interstitial nephritis: Pathogenesis and heterogeneity

Pathogenesis of ICI-AIN is dominated by adaptive immune cells

ICI-AIN is the most common pathological type among ICI-AKI, accounting for 82.8–93.3% of biopsy-confirmed cases.^[27,28] The typical pathological injury pattern consists of diffuse or focal dense lymphomonocytic infiltration within the renal interstitium, often accompanied by tubulitis. The infiltrating cells are predominantly T lymphocytes, with both CD4⁺ helper T cells and CD8⁺ cytotoxic T cells present. This is frequently accompanied by B cells, plasma cells, macrophages, and dendritic cells.^[29-32] The overall pathogenesis of ICI-AIN, dominated by adaptive immune cells, has been shown in Figure 1.

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Figure 1: Schematic overview of the proposed typical pathogenesis of immune checkpoint inhibitor-acute interstitial nephritis. Immune checkpoint inhibitors (ICIs) block inhibitory signaling pathways (e.g., PD-1/PD-L1), breaking immune tolerance and leading to the aberrant activation of pre-existing, autoreactive CD8⁺ TRM cells within the kidney. These activated CD8⁺ TRM cells serve as central drivers, producing large amounts of interferon-gamma (IFN-γ) and CXCL13. IFN-γ acts via the JAK-STAT pathway to upregulate major histocompatibility complex class I (MHC-I) expression on local antigen-presenting cells (such as dendritic cells and macrophages), enhancing antigen presentation and creating an amplifying inflammatory loop. IFN-γ also drives the polarization of macrophages toward a pro-inflammatory phenotype. These macrophages contribute to tissue damage through multiple mechanisms: Secreting matrix metalloproteinases (e.g., MMP12) that disrupt the tubular basement membrane, producing chemokines (CXCL9, CXCL10, CXCL11) that recruit additional CXCR3⁺ inflammatory cells (including CD8⁺ T cells), and supporting local inflammation. Concurrently, CXCL13 promotes B-cell aggregation. This pathogenic cascade results in suppressed oxidative phosphorylation in tubular cells, tubulitis, interstitial infiltration, tubular dysfunction, and ultimately, acute kidney injury characteristic of ICI-AIN. The figure was drawn by BioRender (Science Suite Inc., https://biorender.com/).

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Diffuse lymphomonocytic infiltration and TLS aggregation

Under this type of pathogenesis, which is dominated by adaptive immune cells, there is also diffuse infiltration of lymphoid mononuclear cells [Figure 2a] and the formation of TLS [Figure 2b]. Diffuse lymphocyte infiltration and TLS can coexist, while TLS formation can be conceptualized as the organization of diffuse lymphocytic infiltrates into localized aggregates, a phenomenon frequently observed in ICI-AIN biopsies.^[48,49]

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Figure 2: Histopathological spectrum and heterogeneity of immune checkpoint inhibitor-acute interstitial nephritis (AIN) dominated by adaptive immune cells. (a) Typical AIN: Representative image showing diffuse interstitial lymphomonocytic infiltration accompanied by tubulitis. The arrows indicate lymphocytes invading the tubular epithelium (tubulitis) (PAS staining, scale bar = 50 μm). (b) Tertiary lymphoid structure (TLS) Formation: The renal interstitium exhibits well-organized aggregates of immune cells forming TLS. The arrow indicates a mature or maturing TLS cluster (Hematoxylin and Eosin [H&E] staining, scale bar = 50 μm).

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A subset of ICI-AIN cases exhibits marked histopathological features often accompanied by the formation of TLS.^[49] TLS is ectopic lymphoid tissue that develops in non-lymphoid organs under conditions of chronic inflammation or autoimmune disease, structurally and functionally resembling secondary lymphoid organs. They represent the evolution of a local immune response from an initial/inciting inflammatory event into a highly organized, autonomous, and persistent inflammatory center, driven by a self-sustaining positive feedback loop.^[50-53] The function and activity of TLS critically influence disease progression, yet exhibit a dual role with divergent clinical associations that are highly dependent on the pathological context. In the tumor microenvironment, TLS formation is generally associated with stronger anti-tumor immune responses, better responses to ICI therapy and improved patient survival, thus considered a favorable prognostic marker.^[54-56] Conversely, in kidney diseases, including ICI-AIN, the presence of TLS is associated with persistent tissue inflammation, a more significant decline in renal function, and worse clinical outcomes.^[49]

The formation of TLS in ICI-AIN is closely linked to specific chemokine axes, particularly CXCR5/CXCL13 and CCR7/CCL19/CCL21 [Figure 3], which orchestrate the homing and spatial aggregation of B and T lymphocytes.^[57,58] In ICI-AIN, renal tissue expression of CXCL13 and CCL19 is significantly upregulated compared to acute tubular necrosis or hypertensive nephropathy.^[49] Spatially resolved transcriptomic analysis further suggests that interactions within the CXCR5/CXCL13 and CCR7/CCL19 axes are most pronounced inside TLS-like immune niches, confirming their central role in the spatial organization of TLS in this disease.^[43] It has been established that T cells within TLS produce pro-inflammatory cytokines such as IFN-γ to induce inflammatory reactions in surrounding tubular epithelial cells and fibroblasts.^[59] Moreover, these activated parenchymal cells in turn produce additional chemokines such as CXCL9, CXCL10, and CXCL13, establishing a self-amplifying positive feedback loop that perpetuates lymphocyte recruitment and sustains immune infiltration within the kidney.^[60]

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Figure 3: Mechanism of tertiary lymphoid structures in kidney disease. TLS formation is orchestrated by specific chemokine axes. The CXCR5/CXCL13 axis mediates B cell homing and aggregation, while the CCR7/CCL19/CCL21 axis facilitates T cell recruitment and compartmentalization. Within these organized immune aggregates, activated B cells interact with T follicular helper cells via interleukin (IL)-21 signaling, promoting B cell differentiation toward plasmablasts and plasma cells, with evidence of germinal center (GC)-like maturation. Local autoantibody production by plasma cells may contribute to tissue injury. Concurrently, CD8⁺ T cells within the TLS microenvironment produce effector cytokines (TNF-α, IFN-γ) that act on surrounding tubular epithelial cells and fibroblasts. These structural cells, in turn, produce additional chemokines (CXCL9, CXCL10, CXCL11, and CXCL13), establishing a self-amplifying positive feedback loop that perpetuates lymphocyte recruitment. Activated fibroblasts drive extracellular matrix deposition, leading to interstitial fibrosis and progressive kidney function loss. The figure was drawn by BioRender (Science Suite Inc., https://biorender.com/).

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Once established, a highly organized TLS constitutes a functional local immune microenvironment, particularly when exhibiting GC-like structures.^[61] Although histopathological evaluation of renal biopsies from ICI-AIN patients has provided clear evidence of TLS formation, the presence of fully mature GCs remains to be fully confirmed. Histologically, these structures show preliminary organized lymphocyte aggregates often accompanied by adjacent CD20⁺ B cell and CD3⁺ T cell zones. At the molecular level, gene expression analysis reveals an activated B cell state, often accompanied by high expression of REL, LTB, CD20, CXCR5, and BCL6, along with a differentiation trend toward plasmablasts (expressing IRF4 and CD62L). The concurrent expression of GC-associated markers such as VCAM1 and TNFRSF17/BCMA suggests these structures are developing toward a GC phenotype.^[49] This evolving maturity is of central importance because the functional capacity of TLS is closely linked to its degree of organization. Highly mature TLS, especially those containing GCs, may exacerbate disease progression by continuously producing autoantibodies and activating autoreactive T cells.^[62-64] Consequently, this persistent and organized local immune response becomes relatively self-sustaining, no longer dependent solely on systemic immune input, and is notoriously resistant to complete eradication with systemic immunosuppressive therapies such as corticosteroids. This underscores the critical need for targeted therapeutic strategies that can disrupt the local TLS niche or its maintenance signals to effectively manage this refractory form of ICI-AIN.

Pathogenesis of ICI-AIN is dominated by innate immune cells

ICI-AIN exhibits significant immunopathological heterogeneity, which manifests as variations in disease severity, clinical outcomes, dominant immune cell composition, distinct histological patterns, and the activation of diverse inflammatory pathways. Kidney biopsies have revealed distinct patient clusters, among which a neutrophil-rich subtype is associated with particularly severe acute kidney injury, systemic inflammation, complement activation, and poorer response to corticosteroid therapy.^[48,65] Moreover, the pathogenesis dominated by neutrophil infiltration is mutually exclusive from the pathogenesis of other types at the same time point. Immunophenotyping analyses indicate that ~20–30% of ICI-AIN patients present with this pattern. Histologically, it is defined by substantial neutrophil infiltration within the renal interstitium and tubules, microscopically resembling acute pyelonephritis [Figure 4].^[65] Clinically, patients with this subtype suggest a more pronounced systemic inflammatory response, evidenced by significantly elevated serum C-reactive protein levels and neutrophil-to-lymphocyte ratio, along with more severe acute kidney injury, reflected by higher peak serum creatinine levels. Furthermore, this group shows a significantly lower response rate to first-line glucocorticoid therapy (~38%) and carries a higher risk of disease relapse.

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Figure 4: Histopathological spectrum of neutrophil-dominant infiltration. A distinct subtype often accompanied by prominent neutrophilic aggregates within the interstitium. The arrow highlights the infiltrating neutrophils (H&E staining, scale bar = 50 μm).

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The potential pathophysiology of this subtype is closely linked to significant activation of the complement pathway, particularly the C5a/C5aR1 axis. This is supported by a strong positive correlation between urinary C5a levels and the degree of activated neutrophil infiltration in renal tissue. These findings suggest that in this poor-prognosis subset, pathogenesis may be primarily orchestrated by an aberrant, complement-driven innate immune response, rather than the classic IFN-γ-centered adaptive immune axis.^[48] As a potential component of innate immunity, the complement system generates activation products such as C5a, a potent chemoattractant that effectively recruits neutrophils to sites of inflammation. Upon recruitment and activation by C5a, neutrophils release a variety of effector molecules, including reactive oxygen species, myeloperoxidase, and proteolytic enzymes. In addition, they can cause direct damage to tubular pithelial cells and interstitial cells through mechanisms such as the formation of neutrophil extracellular traps, ultimately leading to cellular necrosis and apoptosis. This distinct immunopathogenic mechanism underscores the need for tailored diagnostic and therapeutic strategies, such as targeting the complement pathway, to improve outcomes for this high-risk patient subgroup.

Pathogenesis of ICI-AIN is dominated by both adaptive and innate immune cells

A small subset of AIN cases induced by ICIs, particularly by CTLA-4 inhibitors such as ipilimumab, can present as a rare histopathological variant known as “granulomatous interstitial nephritis (GIN).” Granuloma formation is generally described as a highly structured, chronic inflammatory response to persistent, non-eliminable stimuli (e.g., pathogens or foreign materials). It is often accompanied by the aggregation of activated macrophages, which can fuse into multinucleated giant cells, surrounded by lymphocytes.^[66-69] Granulomas and TLS can coexist in the chemical-induced lupus mouse model and tuberculosis patients.^[70,71]

Current understanding of ICI-associated GIN (ICI-GIN) is primarily based on a limited number of case reports, as summarized in Table 1. These documented cases involve 12 patients aged 55–78 years,^{[66,67,72-78]} most with metastatic melanoma, who were treated with ICIs such as ipilimumab (anti-CTLA-4), nivolumab (anti-PD-1), or combination therapy. Renal injury typically manifests during treatment as AKI, characterized by elevated serum creatinine and mild urinary abnormalities. While most patients showed improvement or partial recovery of renal function following ICI discontinuation and corticosteroid therapy, a subset, particularly those receiving combination therapy or with histology revealing necrotizing vasculitis, experienced poor outcomes, including progression to dialysis dependence. A systematic review of 261 patients further indicated that individuals on combination immunotherapy (e.g., anti-CTLA-4 plus anti-PD-1/PD-L1) exhibited a higher prevalence of necrotizing granulomas, along with more severe clinical presentations and greater therapeutic complexity.^[79] Overall, early recognition, prompt cessation of ICIs, and timely initiation of immunosuppressive therapy remain critical for the effective management of ICI-GIN.

The immune pathogenesis of ICI-GIN remains incompletely understood. While granuloma formation is generally linked to Th1/Th17-driven pathways that activate and recruit monocytes/macrophages,^[80-83] recent case reports and systematic studies on ICI-GIN or associated vasculitis reveal a distinct local immune microenvironment. Immunophenotyping of renal biopsies suggests that the inflammatory infiltrate differs from the CD4⁺ T-cell predominance typically observed in sarcoidosis or infection-induced GIN.^[84,85] Instead, CD8⁺ T cells significantly outnumber CD4⁺ T cells and exhibit features of antigen-independent activation, often accompanied by high expression of cytotoxic mediators Granzyme B and TIA-1 but low or absent expression of classic activation markers CD25 and the inhibitory receptor PD-1, suggesting a cytokine-driven (e.g., IL-2) rather than antigen-specific pathological activation. Furthermore, CD163⁺ macrophages, typically associated with an alternatively activated phenotype, constitute a major component within GIN and vasculitic lesions.^[66] Notably, the extent of CD163⁺ macrophage interstitial infiltration has been negatively correlated with initial estimated glomerular filtration rate at biopsy (r = −0.6, P = 0.003), reflecting greater severity of renal injury at disease onset and association with kidney fibrosis.^[86] This pathogenic role is mechanistically supported by the high expression of pro-fibrotic and pro-inflammatory mediators within these cells. For instance, MMP12, a key protease implicated in extracellular matrix remodeling and fibrosis, is highly expressed by CD163⁺ macrophages in ICI-AIN, and its pharmacological inhibition attenuates renal injury and fibrosis in experimental models.^[47] In contrast to this prominent infiltration of effector cells – notably CD8⁺ T cells and CD163⁺ macrophages – there is a marked scarcity or virtual absence of regulatory T cells (Tregs) locally.^[66] Consequently, the immune microenvironment in ICI-GIN appears to exhibit a distinct “effector-suppressor” imbalance. This proposed imbalance, which is dominated by cytotoxic CD8⁺ T cells and CD163⁺ macrophages, with a relative scarcity or absence of Tregs, is hypothesized to collectively contribute to the persistent inflammation and tissue damage observed in this pathological subtype. However, the precise causal relationships and underlying molecular drivers remain to be fully elucidated.

Clinical application strategies and future directions

In summary, ICI-AIN represents a heterogeneous immunopathological spectrum often accompanied by distinct pathogenic axes, including the adaptive immune/ organized TLS axis, the complement/neutrophil axis, and the macrophage/T cell/fibroblast network driving GIN formation. These immunophenotypic subtypes are significantly associated with different clinical outcomes, such as glucocorticoid responsiveness, relapse risk, and long-term renal function. Whether these three pathogenic mechanisms can interconvert in the same patient during disease progression remains an open question that warrants further investigation.

It is important to emphasize that the classification of ICIAIN is based on emerging evidence from small, single-center studies and case series. At present, no standardized, prospectively validated diagnostic criteria or subtype-specific treatment algorithms exist for these immune subtypes. Given the current state of evidence, it would be premature to propose distinct therapeutic strategies for each subtype. Instead, all subtypes should be managed according to the established overall treatment principles for ICI-AIN, which are well-supported by the literature. First, concomitant medications that may induce acute tubulointerstitial nephritis, such as proton pump inhibitors (PPIs) and non-steroidal anti-inflammatory drugs (NSAIDs), should be discontinued. ICIs should be temporarily withheld and may be reconsidered after recovery of kidney function. First-line therapy consists of corticosteroids, with a recommended dose of prednisone equivalents of 0.5–1 mg/kg per day, tapered over 4–6 weeks. For steroid-resistant or relapsing cases, infliximab or mycophenolate mofetil may be considered; however, data on these agents are limited. Other immunosuppressants such as azathioprine, cyclophosphamide, or cyclosporine are not routinely recommended.^[3] The immune subtypes described herein are presented primarily as preliminary pathological observations with potential prognostic significance and broader clinical relevance. Future prospective studies are therefore urgently needed to determine whether these distinct subtypes truly warrant carefully individualized differential therapeutic approaches.

Furthermore, the specific immune network architectures underlying these subtypes and their mechanistic links to clinical features remain largely undefined. Key unresolved questions include how CD8⁺ TRM cells establish precise spatial adjacency, physical contact, and functional cooperation with specific CD4⁺ T cell subsets, functionally diverse myeloid cells, dendritic cells, and B cells within distinct renal compartments. Furthermore, as the current spatial transcriptomics study on the pathogenic mechanism of CD8⁺ TRM cells is still in the preprint stage, its conclusions are still preliminary. Furthermore, the research on the immune microenvironment of ICI-GIN is based solely on single-center small-sample case reports, and further large-sample verification is still needed. Regarding epidemiological frequency, due to the limited data currently available, there is no clear literature reference for the precise incidence rates of each subtype. The relative proportion of subtype dominated by neutrophils is derived from a single-center retrospective cohort, and its generalizability requires validation in future multicenter studies.

To address this knowledge gap, future research should leverage integrated multimodal approaches, combining high-resolution spatial transcriptomics with high-parameter multiplex immunofluorescence technologies.^[87] This will enable in situ validation of key immune molecule co-localization and interactions at single-cell resolution, systematically elucidating the precise cellular composition, spatial organization, and dynamic regulatory logic of immune networks in ICI-AIN. Such insights are essential for translating immunopathological heterogeneity into actionable therapeutic targets and personalized management strategies.

Differential diagnosis and biomarkers for ICI-AIN and classic drug-induced AIN

In the clinical management of ICI-AIN, understanding its complex relationship with classic drug-induced AIN, particularly that triggered by commonly used medications such as PPIs, NSAIDs, and antibiotics, represents a significant challenge in nephrology and oncology.^[88] Multiple large-scale cohort studies have confirmed that concurrent use of PPIs or NSAIDs during ICI therapy significantly increases the risk of ICI-AIN, with PPIs clearly identified as one of the most important and potentially modifiable risk factors (odds ratio = 1.84).^[89,90]

Clinicopathologically, these two forms of AIN share overlapping features, including interstitial infiltrates predominantly composed of T lymphocytes. Transcriptional analyses reveal that gene expression for IL2RA (encoding the IL-2 receptor alpha chain, a marker of T cell activation), along with IL-2 signaling and TCR signaling pathway scores, is significantly elevated in kidney tissue from patients with ICI-AIN compared to controls with acute tubular injury or histologically normal tissue. Notably, these elevations are similarly observed in classical drug-induced AIN, with no significant differences between the two groups, collectively indicating a state of T-cell activation within the renal parenchyma in ICI-AIN, mirroring the pattern seen in classic drug-induced immune injuries.^[91]

However, distinct features also exist. For example, eosinophilic infiltration is relatively uncommon in ICI-AIN, contrasting with classic drug-induced AIN caused by agents such as beta-lactam antibiotics.^[92,93] Moreover, ICI-AIN often suggests a higher proportion of cortical involvement, more prominent moderate-to-severe tubulitis, and more frequent positive expression of PD-1/PD-L1 immune checkpoint molecules in renal tissue.^[94] Multiple studies confirm that PD-1/PD-L1 expression in renal tissue is a distinctive feature of ICI-AIN compared to classic drug-induced AIN. The majority of ICI-AIN cases reveal PD-1-positive inflammatory cells and PD-L1-positive tubular epithelial cells, whereas such expression is rare in non-ICI AIN. This characteristic suggests a potential pathophysiological role for the PD-1/PD-L1 pathway in ICI-AIN and offers a potential marker for histopathological differentiation between these two entities.^[94,95]

Furthermore, non-invasive urinary biomarkers reveal molecular-level differences between the ICI-AIN and nonICI-AIN. Urinary soluble PD-1 is significantly elevated in ICI-AIN compared with both non-ICI-AIN and classic drug-induced AIN and acute tubular necrosis, demonstrating high sensitivity and usefulness for screening.^[96] Meanwhile, a characteristic panel of chemokines is upregulated in ICI-AIN. Urinary CXCL10, CXCL11, and CCL5 are significantly higher in ICI-AIN than in non-ICI-AIN, providing strong discriminatory diagnostic value. Importantly, the dynamics of these molecules hold clinical relevance. After effective treatment, levels of CXCL9, CXCL10, and CXCL11 decline significantly. Moreover, Spearman correlation between the early change in urinary chemokine levels (defined as delta biomarker = concentration at diagnosis − concentration at first follow-up within 30–90 days) and the serum creatinine ratio at 1 year (serum creatinine at diagnosis/serum creatinine at 1-year follow-up) showed a significant positive correlation for both CXCL9 (r = 0.706, P = 0.013) and CXCL10 (r = 0.629, P = 0.032), indicating that earlier and greater declines in these chemokines within 30–90 days of treatment are associated with better renal function recovery at 1 year.^[97] However, this analysis reported only a trend and did not define a specific clinical cutoff value; prospective validation studies are required to establish optimal sampling time points (e.g., day 7, day 30) and thresholds (e.g., a >50% decline from baseline) in further studies.

Despite these promising findings, several critical gaps must be acknowledged before these biomarkers can be integrated into routine clinical practice. First, the specificity of these urinary biomarkers, particularly CXCL9 and CXCL10, against other concurrent immune-related adverse events (irAEs) has not been established. Since CXCL9 and CXCL10 are IFN-γ-induced chemokines, systemic inflammation from concurrent colitis or pneumonitis could potentially elevate their circulating levels, leading to false-positive results in the urine. Dedicated studies comparing urinary biomarker profiles in patients with ICI-AIN versus those with extrarenal irAEs are needed to validate kidney-specific utility.

Second, moving from a descriptive biomarker panel to a clinically actionable diagnostic and monitoring tool is important. The novel biomarkers (usPD-1 + CXCL11) with traditional clinical indicators (serum creatinine, C-reactive protein, urine white blood cell count) distinguished ICIAIN from acute tubular necrosis, achieving an area under the curve of 0.91, which was superior to any single novel indicator or previous clinical indicator model.^[97] These findings suggest that these chemokines serve not only as diagnostic aids but also as potential dynamic biomarkers for monitoring disease activity, assessing treatment response, and predicting renal prognosis.^[97,98] Other potential biomarkers for monitoring include urinary MCP-1,^[19] serum soluble IL-2 receptor,^[91] and urinary TNF-α.^[99] Furthermore, complement activation fragments (e.g., C3d, C5a) may be specific to high-risk neutrophil-rich subtypes. In the future, in large sample size cohorts, novel diagnostic marker combinations that can distinguish ICI-AIN from classic drug-induced AIN can be sought. At the same time, traditional routine indicators can be combined for diagnosis and screening. Routine indicators include inflammatory indicators (such as serum creatinine, C-reactive protein, and urine white blood cell count), imaging features (such as the average standardized uptake value of renal cortex in F¹⁸-FDG PET-CT examination^[100]), and renal pathological features (such as PD-1/PD-L1 expression status). Future studies should also assess whether a multi-marker panel (e.g., usPD-1 + usMCP-1 + serum creatinine + average standardized uptake value of renal cortex) offers superior prognostic performance compared with individual markers alone. All proposed combinations are currently hypothetical and require prospective validation in large, multicenter cohorts. If the non-invasive diagnostic result clearly indicates ICI-AIN, empirical treatment can be initiated; only when the non-invasive model cannot confirm the diagnosis or when other causes are suspected, renal pathological testing should be conducted.

Connection between ICI-AIN and classic drug-induced AIN

The relationship between ICI-AIN and classic drug-induced AIN is increasingly recognized in clinical practice, although its underlying mechanisms remain incompletely understood. In patients with ICI-AIN, the presence of circulating T cells demonstrating reactivity to specific drugs (e.g., lansoprazole) has been detected using the drug lymphocyte stimulation test, directly confirming the existence of drug-specific T cells.^[101] The discontinuation of these concomitant medications has been associated with clinical improvement in many reported cases.^[28,75,102] For example, after using pantoprazole for 6 months, a patient developed AIN and was admitted to the hospital. After discontinuing the medication, his renal function improved. However, half a year later, due to digestive problems, he used omeprazole again, and the AIN occurred once more.^[103] Based on the above research results, we believe that the “two-hit model”, a pathophysiological hypothesis, can, to some extent, explain the relationship between the ICI-AIN and classic drug-induced AIN. This model suggests that classical drug-induced renal injury may create a susceptible microenvironment for ICI-mediated immune reactions. In the first stage, when a patient uses a drug with AIN-inducing potential, such as a PPI, the drug or its metabolites can act as haptens, binding to peri-tubular proteins in the kidney, thereby potentially activating a specific memory T lymphocyte response against the neo-antigen. However, this response is normally held in a tolerized state by the local immune regulatory networks of the kidney, as described previously. During the second stage, when the patient receives the ICI, the blockade of the PD-1/PD-L1 and other immune checkpoint pathways is thought to disinhibit and terminate tolerance in these pre-sensitized, drug-specific T cells. This is hypothesized to lead to their reactivation and clonal expansion, resulting in an uncontrolled, T cell-mediated, targeted inflammatory response, culminating in clinically apparent AIN.^[104] However, it is critical to emphasize that no direct experimental validation – either in an animal model or in a prospective human study – currently exists to prove that ICI-induced T-cell reactivation specifically targets drug-derivatized renal antigens.

Therefore, PPI misuse should be strictly avoided in clinical practice, and each clinical encounter should include an assessment of whether PPI therapy is truly necessary for the patient. The dose and duration of treatment should be limited to the minimum effective range, as the risk of chronic kidney disease may be positively correlated with both the dose and duration of PPI exposure.^[103] When gastroprotection is deemed necessary, consider switching to an H2 receptor antagonist as an alternative.^[89,105] If a patient has previously experienced ICI-AIN and rechallenge with ICIs is being considered, cautious avoidance of PPIs and other drugs known to induce AIN (such as NSAIDs and antibiotics) is warranted.^[104] A more aggressive pursuit of kidney biopsy is warranted in ICI-treated patients who develop AKI while receiving PPI/NSAID therapy, as drug discontinuation alone may not suffice.^[1,92] Multidisciplinary collaboration between oncology and nephrology should also be established.

While the relationship between ICI-AIN and classic drug-induced AIN is increasingly recognized, several key questions must be addressed to improve clinical management. First, a more detailed mechanistic understanding is needed to elucidate how drugs such as PPIs are processed, presented, and ultimately induce a specific pool of memory T cells, as well as the precise mechanisms by which this pool is activated and expands upon loss of immune tolerance due to ICI therapy. Second, a systematic comparison of whether the severity or specificity of AIN induced by different therapeutic drugs (e.g., antibiotics, NSAIDs vs. PPIs) differs in the presence of ICIs is currently lacking. This gap hinders the refinement of risk stratification and management strategies. Finally, the integration and validation of promising noninvasive biomarkers represent a crucial challenge. This requires verifying their diagnostic accuracy, early warning potential, and utility in monitoring treatment response in large-scale, multicenter cohorts. Establishing disease-specific diagnostic thresholds in the context of ICI therapy is essential. The successful application of these biomarkers holds the promise of significantly reducing reliance on the invasive gold standard of kidney biopsy, enabling early noninvasive diagnosis of ICI-AIN.