Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors

Naba Farooqui; Mark Zaidi; Lisa Vaughan; Trevor D McKee; Eram Ahsan; Kevin D Pavelko; Jose C Villasboas; Svetomir Markovic; Timucin Taner; Nelson Leung; Haidong Dong; Mariam P Alexander; Sandra M Herrmann

doi:10.1016/j.ekir.2022.11.020

Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors

Kidney Int Rep. 2022 Dec 5;8(3):628-641. doi: 10.1016/j.ekir.2022.11.020. eCollection 2023 Mar.

Authors

Naba Farooqui¹, Mark Zaidi², Lisa Vaughan³, Trevor D McKee^{2

4}, Eram Ahsan¹, Kevin D Pavelko⁵, Jose C Villasboas⁶, Svetomir Markovic⁷, Timucin Taner^{5

8}, Nelson Leung¹, Haidong Dong⁵, Mariam P Alexander⁹, Sandra M Herrmann¹

Affiliations

¹ Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.
² Department of Medical Biophysics, University of Toronto, Ontario, Canada.
³ Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Deciphex Inc., Chicago, Illinois, USA.
⁵ Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA.
⁶ Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.
⁷ Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
⁸ Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA.
⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) induce impressive antitumor responses but may lead to acute kidney injury (AKI) associated with ICI therapy (AKI-ICI). Biomarkers distinguishing AKI-ICI from AKI because of other causes (AKI-other) are currently lacking. Because ICIs block immunoregulatory pathways, we hypothesized that biomarkers related to immune cell dysregulation, including tumor necrosis factor alpha (TNF-α) and other markers of B and T cell activation in the systemic circulation and kidney tissue, may aid with the diagnosis of AKI-ICI.

Methods: This is a prospective study consisting of 24 participants who presented with AKI during ICI therapy, adjudicated to either have AKI-ICI (n = 14) or AKI-other (n = 10). We compared markers of kidney inflammation and injury (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1) as well as plasma and urine levels of T cell-associated cytokines (TNF-α, interferon-γ, interleukin (IL)-2, IL-4, IL-6, IL-8, IL-9, and IL-10) between groups. We also compared T-cell responses in the systemic circulation and in kidney tissue across groups, using mass cytometry systems.

Results: We observed increase in several specific immune cells, including CD4 memory, T helper cells, and dendritic cells in the kidney tissue, as well as in the urine cytokines IL-2, IL-10, and TNF-α, in patients who developed AKI-ICI compared to patients with AKI-other (P < 0.05 for all). The discriminatory ability of TNF-α on AKI cause was strong (area under the curve = 0.814, 95% confidence interval: 0.623-1.00. The CD4+ T cells with memory phenotype formed the dominant subset.

Conclusion: These results suggest that specific T-cell responses and their respective cytokines may be indicative of AKI associated with ICI therapy and may help to differentiate AKI-ICI from AKI-other. Urine TNF-α is a promising biomarker for AKI-ICI, which is most often caused by acute interstitial nephritis (AIN), and TNF-α pathway may serve as a potential target for therapeutic intervention.

Keywords: acute interstitial nephritis; acute kidney injury; biomarkers; cytokines; immune cell phenotyping; immune checkpoint inhibitors.