Background and objectives: Immune checkpoint inhibitors are increasingly used to treat various malignancies but their application in kidney transplant patients is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathological features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis.
Design, setting, participants, and measurements: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T-cell mediated rejection (TCMR) and immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN), and an independent 50-sample validation cohort comprising ICI-AIN, immune checkpoint inhibitor-associated T-cell mediated rejection (ICI-TCMR), immune checkpoint inhibitor-associated crescentic glomerulonephritis, drug-induced acute interstitial nephritis (Drug-AIN), BK virus nephropathy, and normal biopsies.
Results: Significant molecular overlap was observed between ICI-AIN and TCMR. Nevertheless, IFI27, an interferon-alpha induced transcript, was identified and validated as a novel biomarker for differentiating ICI-TCMR from ICI-AIN (validation cohort: P<0.001, AUC=100%, accuracy=86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, ICI-TCMR and ICI-AIN both demonstrated relatively more molecular overlap with Drug-AIN than TCMR, suggesting potential dominance of hypersensitivity mechanisms in these entities.
Conclusions: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and AIN, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.
Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma
