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 immunoregulatory pathways, we hypothesized that biomarkers related to immune cell dysregulation, including tumor necrosis factor alpha (TNF-a) 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-a, interferon -g, 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-a, in patients who developed AKI-ICI compared to patients with AKI-other (P < 0.05 for all). The discriminatory ability of TNF-a on AKI cause was strong (area under the curve = 0.814, 95% confidence interval: 0.623-1.00. The CD4 thorn 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-a is a promising biomarker for AKI-ICI, which is most often caused by acute interstitial nephritis (AIN), and TNF-a pathway may serve as a potential target for therapeutic intervention.