TY - JOUR
T1 - Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors
AU - Farooqui, Naba
AU - Zaidi, Mark
AU - Vaughan, Lisa
AU - McKee, Trevor D.
AU - Ahsan, Eram
AU - Pavelko, Kevin D.
AU - Villasboas, Jose C.
AU - Markovic, Svetomir
AU - Taner, Timucin
AU - Leung, Nelson
AU - Dong, Haidong
AU - Alexander, Mariam P.
AU - Herrmann, Sandra M.
N1 - Funding Information:
SMH is supported by National Institutes of Health K08 DK118120 from the NIDDK and by Mayo CCaTS grant number UL1TR002377.
Funding Information:
We thank the members of our laboratories for stimulating discussions. We also appreciate the contributions of Mayo Clinic Immune Monitoring Core and other institutional scientific core facilities and administrative assistance during the conduct of our studies. SMH is supported by National Institutes of Health K08 DK118120 from the NIDDK and by Mayo CCaTS grant number UL1TR002377. Concept and design was done by all authors. Acquisition, analysis, or interpretation of data was done by all authors. Drafting of the manuscript wa by NF, LV, MZ, MPA, and SMH. Critical revision of the manuscript for important intellectual content was done by all authors. Statistical analysis was perfomed by NF, LV, and SMH. Preparation of figures and tables was done by NF, LV, MZ, MPA, and SMH. All authors approved the final version of the manuscript, and all are accountable for all aspects of the submitted work.
Publisher Copyright:
© 2022 International Society of Nephrology
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - acute interstitial nephritis
KW - acute kidney injury
KW - biomarkers
KW - cytokines
KW - immune cell phenotyping
KW - immune checkpoint inhibitors
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U2 - 10.1016/j.ekir.2022.11.020
DO - 10.1016/j.ekir.2022.11.020
M3 - Article
AN - SCOPUS:85144950962
SN - 2468-0249
VL - 8
SP - 628
EP - 641
JO - Kidney International Reports
JF - Kidney International Reports
IS - 3
ER -