Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor–Associated Adverse Events. Issue 9 (September 2021)

• Record Type: Journal Article
• Authors: Adam, Benjamin A.; Murakami, Naoka; Reid, Graeme; Du, Katie; Jasim, Ruqaya; Boils, Christie L.; Bu, Lihong; Hill, Peter D.; Murray, Allan G.; Renaudin, Karine; Roufosse, Candice; Weins, Astrid; Wen, Kevin; Riella, Leonardo V.; Mengel, Michael
• Is Part Of: Clinical journal of the American Society of Nephrology. Volume 16:Issue 9(2021)
• Page Start: 1376
• Page End: 1386
• Publication Date: 2021-09
• Subjects: kidney transplantation -- drug nephrotoxicity -- acute rejection -- gene expression -- histopathology -- cancer -- immune checkpoint inhibitors -- gene expression profiling -- allografts
• DOI: 10.2215/CJN.00920121
• Languages: English
• ISSNs: 1555-9041

Abstract

Visual Abstract: Abstract : Background and objectives: Immune checkpoint inhibitors are increasingly used to treat various malignancies, but their application in patients with kidney transplants is complicated by high allograft rejection rates. Immune checkpoint inhibitor–associated rejection is a novel, poorly understood entity demonstrating overlapping histopathologic 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, & 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 and immune checkpoint inhibitor–associated acute interstitial nephritis and an independent 50-sample validation cohort comprising immune checkpoint inhibitor–associated acute interstitial nephritis, immune checkpoint inhibitor–associated T cell–mediated rejection, immune checkpoint inhibitor–associated crescentic GN, drug-induced acute interstitial nephritis, BK virus nephropathy, and normal biopsies. Results: Significant molecular overlap was observed between immune checkpoint inhibitor–associated acute interstitial nephritis and T cell–mediated rejection. Nevertheless, IFI27, an IFN- α– induced transcript, was identified and validated as a novel biomarker for differentiating immune checkpoint inhibitor–associated T cell–mediated rejection from immune checkpoint inhibitor–associated acute interstitial nephritis (validation cohort: P <0.001, area under the receiver operating characteristic curve =100%, accuracy =86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, immune checkpoint inhibitor–associated T cell–mediated rejection and immune checkpoint inhibitor–associated acute interstitial nephritis both demonstrated relatively more molecular overlap with drug-induced acute interstitial nephritis than T cell–mediated rejection, 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 acute interstitial nephritis, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.