Immune Profiling Identifies High-Risk Neutrophil-Rich Subtype in Checkpoint Inhibitor Nephritis.

INTRODUCTION

Immune checkpoint inhibitor (ICI)-induced acute interstitial nephritis (AIN) (ICI-AIN) is the leading cause of ICI-associated acute kidney injury (AKI). ICI-AIN is characterized by mononuclear immune infiltrates, although the mechanisms behind their toxicity remain unclear. We aimed to characterize these infiltrates in kidney biopsies and assess their correlation with clinical outcomes and therapeutic responses.

METHODS

We retrospectively analyzed 49 biopsy-proven ICI-AIN cases using multiplex immunofluorescence to quantify immune cells (macrophages, neutrophils, B cells, T cells, and plasmocytes). Unsupervised clustering was used to identify patient groups, which we then correlated with clinical presentation and outcomes. Finally, we explored the role of C5a/C5aR1 in neutrophil recruitment.

RESULTS

Unsupervised clustering revealed 3 immune phenotypes as follows: (i) low mononuclear (cluster 1), (ii) high mononuclear (cluster 2), and (iii) neutrophil-rich (cluster 3). Cluster 3 was associated with higher systemic inflammation (C-reactive protein: 84 vs. 15-24 mg/l, P = 0.0002; neutrophil-to-lymphocyte ratio (NLR): 7 vs. 3.2-2.3, P < 0.0001) and more severe initial AKI (peak creatinine: 360 vs. 215-208 μmol/l, P = 0.0001). Histologically, it was marked by granular casts and neutrophilic tubulitis (P < 0.0001). Despite the pyelonephritis-like appearance, urine cultures and metatranscriptomic analysis both ruled out infection. At 12 months, renal response rates to steroids were 93% (cluster 2), 67% (cluster 1), and 38% (cluster 3) (P = 0.004). Relapses occurred more frequently in cluster 3 (38% vs. 11% in cluster 1, 0% in cluster 2, P = 0.01). Urine C5a correlated with C5aR1+ neutrophil infiltration (rho = 0.78).

CONCLUSION

Our findings identify distinct ICI-AIN subtypes, with a neutrophil-rich cluster linked to complement activation and poor prognosis, offering insights into refining diagnosis and treatment strategies.