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. 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. Significant molecular overlap was observed between ICI-AIN and TCMR. Nevertheless, , 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. These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and AIN, biopsy-based measurement of gene expression represents a potential biomarker for differentiating these entities.
About The Expert
Benjamin Adam
Naoka Murakami
Graeme Reid
Katie Du
Ruqaya Jasim
Christie Boils
Lihong Bu
Peter Hill
Allan Murray
Karine Renaudin
Candice Roufosse
Astrid Weins
Kevin Wen
Leonardo Riella
Michael Mengel
References
PubMed