The use of immune checkpoint inhibitors (ICIs) in the treatment of various hematologic and solid malignancies has led to better patient survival. The first ICI to be approved in 2011 was the monoclonal antibody-blocking cytotoxic T-lymphocyte antigen (CTLA)-4 ipilimumab. Activation of CTLA-4, expressed on cytotoxic T lymphocytes, results in downregulation of these cells. Ipilimumab turns off this inhibition, resulting in enhanced cytotoxic T cell function, which results in anti-tumor cell activity. This was followed by inhibitors of programmed cell death protein 1 (PD1), such as nivolumab, pembrolizumab cemiplimab, and dostarlimab that block PD1, and atezolizumab, avelumab, and durvalumab that target programmed death ligand 1 (PD-L1). PD1 is a coinhibitory molecule expressed on T cells, and PD-L1 is expressed on the surface of different tissue types, including tumor cells. The ICIs remove inhibitory signals to allow T cell activation and generation of a robust anti-tumor immune response, which also leads to inflammatory side effects in any organ system, often termed immune-related adverse effects (irAEs).
The incidence of acute kidney injury (AKI) associated with ICI therapy (AKI-ICI) is estimated to be 3%–5%, with acute interstitial nephritis (AIN) being the most common histopathologic finding (1, 2). Prompt recognition and reversal of kidney injury with immunosuppressive therapy remain the mainstays for treatment, hence the need for early detection. A late diagnosis contributes to treatment delays and future consideration for ICI rechallenge to address the underlying malignancy (3). The quest for early diagnosis has led to several research studies to identify risk factors, clinical features, and biomarkers for irAEs. Biomarkers with promising potential for AKI-ICI in two recent studies are summarized in Table 1.
Biomarkers with promising potential for AKI-ICI
A more recent study by Farooqui et al. (4) evaluated blood, urinary cytokines, and immune cell phenotypes in the peripheral blood of 24 patients in an exploratory study. Fourteen patients with AKI-ICI and 10 patients with non-AKI-ICI were evaluated. Of the 14 patients with AKI, 10 had a kidney biopsy showing AIN (4). The goal of the study was to differentiate AKI-ICI from AKI due to other etiologies without the need of a kidney biopsy. Blood and urine cytokines and immune cell phenotypes in the peripheral blood and tissue of patients on ICI therapy at the time of AKI were obtained. The authors found an abundance of specific immune cells, including CD4 memory, T helper (Th), and dendritic cells in the kidney tissue of patients who developed AKI-ICI. Immunophenotyping also revealed strong expression of tumor necrosis factor α (TNF-α) in kidney biopsies. Urine TNF-α, interleukin (IL)-2, and IL-10 were significantly elevated in AKI-ICI compared with AKI not induced by ICI or healthy controls. The study revealed a strong discriminatory ability of the urine TNF-α level (area under the curve [AUC], 0.814; 95% CI, 0.623–1.00) to detect AKI-ICI. The authors also report a strong expression of TNF-α in kidney biopsies, suggesting that TNF-α originates primarily from the kidney in patients with AKI-ICI with pathology demonstrating AIN. This was in line with a similar biomarker study for a clinical diagnosis of AIN in which urine TNF-α was higher in patients with AIN (5).
Studies on biomarkers for AKI-ICI shed light on mechanistic insights to AKI-ICI. Their results imply that a specific T cell response and respective cytokines may be indicative of AKI-ICI and may differentiate AKI-ICI from other etiologies. There continues to be a need to identify biomarkers for optimal management and safe rechallenge of patients with ICI-associated AKI. As precision medicine in kidney diseases is being advocated, studies such as this on a larger scale should be done to combine knowledge of disease mechanisms to identify subsets of patients who may benefit from specific treatment strategies.
References
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Gupta S, et al. Acute kidney injury in patients treated with immune checkpoint inhibitors. J Immunother Cancer 2021; 9:e003467. doi: 10.1136/jitc-2021-003467
- 2.↑
Seethapathy H, et al. The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors. Clin J Am Soc Nephrol 2019; 14:1692–1700. doi: 10.2215/CJN.00990119
- 3.↑
Seethapathy H, et al. Immune checkpoint inhibitors and kidney toxicity: Advances in diagnosis and management. Kidney Med 2021; 3:1074–1081. doi: 10.1016/j.xkme.2021.08.008
- 4.↑
Farooqui N, et al. Cytokines and immune cell phenotype in acute kidney injury associated with immune checkpoint inhibitors. Kidney Int Rep [published online ahead of print December 5, 2022]. https://www.sciencedirect.com/science/article/pii/S2468024922018836
- 5.↑
Moledina DG, et al. Urine TNF-α and IL-9 for clinical diagnosis of acute interstitial nephritis. JCI Insight 2019; 4:e127456. doi: 10.1172/jci.insight.127456
- 6.
Isik B, et al. Biomarkers, clinical features, and rechallenge for immune checkpoint inhibitor renal immune-related adverse events. Kidney Int Rep 2021; 6:1022–1031. doi: 10.1016/j.ekir.2021.01.013
- 7.
Singh S, et al. Tertiary lymphoid structure signatures are associated with immune checkpoint inhibitor related acute interstitial nephritis. JCI Insight [published online ahead of print December 1, 2022]. doi: 10.1172/jci.insight.165108; https://insight.jci.org/articles/view/165108