Gene expression profiling in kidney transplants with immune checkpoint inhibitor–associated adverse events

Benjamin A. Adam, Naoka Murakami, Graeme Reid, Katie Du, Ruqaya Jasim, Christie L. Boils, Lihong Bu, Peter D. Hill, Allan G. Murray, Karine Renaudin, Candice Roufosse, Astrid Weins, Kevin Wen, Leonardo V. Riella, Michael Mengel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1376-1386
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Volume16
Issue number9
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
B.A. Adam reports employment with Alberta Precision Laboratories. C.L. Boils reports employment with Arkana Laboratories. P.D. Hill reports employment with Imperial College Healthcare; receiving honoraria from Genzyme, Otsuka, Roche, and Sanofi; and serving as the chairman of the West London Hospitals Holiday Dialysis Trust. M. Mengel reports consultancy agreements with Novartis and Vitaeris Inc.; ownership interest with Roche; receiving honoraria from CSL Behring, Novartis, and Vitaeris; and serving as a scientific advisor or member of the American Journal of Transplantation editorial board and Novartis. N. Murakami reports receiving honoraria from Natera Inc. G. Reid reports employment with the Manchester University National Health Service (NHS) Foundation Trust. K. Renaudin reports receiving honoraria from GSK and MSD. L.V. Riella reports receiving research funding from Brystol-Meyers Squibb, CareDx, Natera Inc., and Visterra; receiving honoraria from

Publisher Copyright:
© 2021 by the American Society of Nephrology.

Keywords

  • Acute rejection
  • Allografts
  • Cancer
  • Drug nephrotoxicity
  • Gene expression
  • Gene expression profiling
  • Histopathology
  • Immune checkpoint inhibitors
  • Kidney transplantation

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