Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor-Associated Adverse Events

Clin J Am Soc Nephrol. 2021 Sep;16(9):1376-1386. doi: 10.2215/CJN.00920121. Epub 2021 Jul 9.

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.

Keywords: acute rejection; allografts; cancer; drug nephrotoxicity; gene expression; gene expression profiling; histopathology; immune checkpoint inhibitors; kidney transplantation.

MeSH terms

  • Aged
  • Biopsy
  • Female
  • Gene Expression Profiling*
  • Humans
  • Immune Checkpoint Inhibitors / adverse effects*
  • Kidney Transplantation*
  • Male
  • Middle Aged
  • Nephritis, Interstitial / chemically induced*
  • Nephritis, Interstitial / genetics*
  • Nephritis, Interstitial / pathology
  • Postoperative Complications / chemically induced*
  • Postoperative Complications / genetics*
  • Postoperative Complications / pathology

Substances

  • Immune Checkpoint Inhibitors

Supplementary concepts

  • Acute Tubulointerstitial Nephritis