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Immune Profiling Identifies High-Risk Neutrophil-Rich Subtype in Checkpoint Inhibitor Nephritis
Idris Boudhabhay1,2,3,4,5, Helene Lazareth3,6, Julie Oniszczuk7
1Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris Cité, Team Inflammation, Complement and Cancer, Paris, France.
Kidney International Reports
|February 23, 2026
Summary
Immune checkpoint inhibitor-induced acute interstitial nephritis (ICI-AIN) has distinct subtypes. A neutrophil-rich phenotype is linked to severe kidney injury, inflammation, and poorer outcomes, suggesting complement activation plays a role.
Area of Science:
- Nephrology
- Immunology
- Oncology
Background:
- Immune checkpoint inhibitor-induced acute interstitial nephritis (ICI-AIN) is a primary cause of acute kidney injury (AKI) in patients receiving immune checkpoint inhibitors (ICIs).
- The underlying mechanisms of ICI-AIN, particularly the role of immune cell infiltrates, are not fully understood.
- Characterizing these infiltrates is crucial for understanding ICI-AIN pathogenesis and improving patient outcomes.
Purpose of the Study:
- To characterize immune cell infiltrates in kidney biopsies from patients with ICI-AIN.
- To identify distinct ICI-AIN phenotypes based on immune cell composition.
- To correlate these phenotypes with clinical presentation, severity of AKI, and response to therapy.
Main Methods:
- Retrospective analysis of 49 biopsy-proven ICI-AIN cases.
- Multiplex immunofluorescence was used to quantify various immune cells (macrophages, neutrophils, B cells, T cells, plasmocytes).
- Unsupervised clustering identified patient subgroups, which were then correlated with clinical data and outcomes. The role of C5a/C5aR1 in neutrophil recruitment was also explored.
Main Results:
- Three immune phenotypes were identified: low mononuclear, high mononuclear, and neutrophil-rich.
- The neutrophil-rich cluster (cluster 3) showed significantly higher systemic inflammation, more severe initial AKI, and was marked by granular casts and neutrophilic tubulitis.
- Steroid response rates were lower in the neutrophil-rich cluster (38%) compared to the high mononuclear cluster (93%), with more frequent relapses in cluster 3. Urine C5a correlated with neutrophil infiltration.
Conclusions:
- Distinct ICI-AIN subtypes exist, with a neutrophil-rich phenotype associated with complement activation (C5a/C5aR1 pathway) and a poorer prognosis.
- This neutrophil-rich phenotype is linked to increased inflammation, severe AKI, reduced response to steroids, and higher relapse rates.
- These findings highlight the importance of immune cell profiling in ICI-AIN for refining diagnosis and tailoring treatment strategies.
Keywords:
acute interstitial nephritischeckpoint inhibitorscomplementimmune phenotypingimmunotherapyneutrophilMore Related Videos
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