Immune checkpoint inhibitor-induced acute interstitial nephritis characterised by distinct immunophenotypes with potentially different management

Immunophenotyping of immune checkpoint inhibitor (ICI)-induced acute interstitial nephritis (AIN) identified a distinct, neutrophil-infiltrating-rich phenotype, highlighting a subgroup that may respond more effectively to complement inhibition rather than steroid-based strategies. This potentially practice-changing finding suggests that future clinical trials could stratify AIN management based on immunophenotypic profiles, opening the door to more targeted, mechanism-based therapies.

Dr Idris Boudhabhay (Necker Hospital, France) investigated data from 39 patients with biopsy-proven ICI-induced acute interstitial nephritis from 5 French hospitals [1]. Patients were grouped into clusters based on key immune cell populations infiltrating the kidneys (macrophages, neutrophils, B cells, T cells, and plasma cells), as identified with multiplex immunofluorescence.

In total, the researchers determined 3 clusters. Cluster 1 had low densities of T cells, B cells, and macrophages, with almost no neutrophils. In contrast, Cluster 2 had high densities of T cells, B cells, and macrophages, but not neutrophils. Finally, Cluster 3 was characterised by neutrophilic infiltration (P<0.001 compared with Clusters 1 and 2). The 3 clusters showed different histological features: Cluster 1 had more fibrosis with less inflammation; Cluster 2 had a dense infiltrate; and Cluster 3 was characterised by more neutrophilic casts and neutrophilic tubulitis. Overall, patients in Cluster 3 had higher levels of inflammation, significantly more kidney injury, a lower probability of kidney recovery, and a higher probability of relapse. Finally, neither cluster was associated with infections, but urinary complement 5a (C5a) levels tended to be higher in Cluster 3.

“We were able to identify 3 distinct immune phenotypes of ICI-induced acute interstitial nephritis based on the renal immune infiltrates,” concluded Dr Boudhabhay. “Among them, a neutrophil-rich subtype was associated with more severe acute kidney injury, poor response to corticosteroids, and higher risk of relapse, which might be linked to the activation of the C5a/C5a receptor 1 axis, suggesting a complement-driven, non-infectious process. This study may suggest that complement inhibition could represent a therapeutic alternative or steroid-sparing strategy, especially in the neutrophil-rich form.”

1. Boudhabhay I, et al. Immune phenotyping of checkpoint inhibitor-induced acute interstitial nephritis uncovers distinct profiles associated with clinico-biological features, treatment response and outcome. 62nd ERA Congress, 4–7 June 2025, Vienna, Austria.

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Posted on 22 August 2025