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

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 immunoregu...

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Autores principales: Farooqui, Naba, Zaidi, Mark, Vaughan, Lisa, McKee, Trevor D., Ahsan, Eram, Pavelko, Kevin D., Villasboas, Jose C., Markovic, Svetomir, Taner, Timucin, Leung, Nelson, Dong, Haidong, Alexander, Mariam P., Herrmann, Sandra M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014345/
https://www.ncbi.nlm.nih.gov/pubmed/36938084
http://dx.doi.org/10.1016/j.ekir.2022.11.020
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author Farooqui, Naba
Zaidi, Mark
Vaughan, Lisa
McKee, Trevor D.
Ahsan, Eram
Pavelko, Kevin D.
Villasboas, Jose C.
Markovic, Svetomir
Taner, Timucin
Leung, Nelson
Dong, Haidong
Alexander, Mariam P.
Herrmann, Sandra M.
author_facet Farooqui, Naba
Zaidi, Mark
Vaughan, Lisa
McKee, Trevor D.
Ahsan, Eram
Pavelko, Kevin D.
Villasboas, Jose C.
Markovic, Svetomir
Taner, Timucin
Leung, Nelson
Dong, Haidong
Alexander, Mariam P.
Herrmann, Sandra M.
author_sort Farooqui, Naba
collection PubMed
description 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.
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spelling pubmed-100143452023-03-16 Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors Farooqui, Naba Zaidi, Mark Vaughan, Lisa McKee, Trevor D. Ahsan, Eram Pavelko, Kevin D. Villasboas, Jose C. Markovic, Svetomir Taner, Timucin Leung, Nelson Dong, Haidong Alexander, Mariam P. Herrmann, Sandra M. Kidney Int Rep Clinical Research 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. Elsevier 2022-12-05 /pmc/articles/PMC10014345/ /pubmed/36938084 http://dx.doi.org/10.1016/j.ekir.2022.11.020 Text en © 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology. https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Clinical Research
Farooqui, Naba
Zaidi, Mark
Vaughan, Lisa
McKee, Trevor D.
Ahsan, Eram
Pavelko, Kevin D.
Villasboas, Jose C.
Markovic, Svetomir
Taner, Timucin
Leung, Nelson
Dong, Haidong
Alexander, Mariam P.
Herrmann, Sandra M.
Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title_full Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title_fullStr Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title_full_unstemmed Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title_short Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
title_sort cytokines and immune cell phenotype in acute kidney injury associated with immune checkpoint inhibitors
topic Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10014345/
https://www.ncbi.nlm.nih.gov/pubmed/36938084
http://dx.doi.org/10.1016/j.ekir.2022.11.020
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