Abstract
Immune checkpoint inhibitors (ICIs) are a novel class of immunotherapy drugs that have improved the treatment of a broad spectrum of cancers as metastatic melanoma, non-small lung cancer or renal cell carcinoma. These humanized monoclonal antibodies target inhibitory receptors (e.g. CTLA-4, PD-1, LAG-3, TIM-3) and ligands (PD-L1) expressed on T lymphocytes, antigen presenting cells and tumor cells and elicit an anti-tumor response by stimulating immune system. Nevertheless, the improved overall survival is complicated by the manifestation of Immune-related Adverse Effects (irAEs). During treatment with ICIs, the most common adverse kidney effect is represented by the development of acute kidney injury (AKI) with the acute tubulointerstitial nephritis as recurrent histological feature. The mechanisms involved in ICIs-induced AKI include the re-activation of effector T cells previously stimulated by nephrotoxic drugs (i.e. by antibiotics), the loss of tolerance versus self-renal antigens, the increased PD-L1 expression by tubular cells or the establishment of a pro-inflammatory milieu with the release of self-reactive antibodies. For renal transplant recipient treated with ICIs, the increased incidence of rejection is a serious concern. Therefore, the combination of ICIs with mTOR inhibitors represents an emerging strategy. Finally, it is relevant to anticipate which patients under ICIs would experience severe irAEs and from a kidney perspective, to predict patients with higher risk of AKI. Here, we provide a detailed overview of ICIs-related nephrotoxicity and the recently described multicenter studies. Several factors have been reported as biomarkers of ICIs-irAEs, in this review we speculate on potential biomarkers for ICIs-associated AKI.
Highlights
Cancer immunotherapy encompasses a number of different treatments aimed at stimulating the immune system in order to promote the recognition and the elimination of tumor cells [1]
The main mechanisms involved in the T cell modulation are the suppression of potential autoreactive naïve- T cell at initial stages in lymph nodes, or in later phases the T cell deactivation in peripheral tissues (Figure 1)
One cytotoxic Tlymphocyte–associated antigen 4 (CTLA-4) inhibitor and five programmed death 1 (PD-1)/PD-L1 inhibitors have been approved by the Food and Drug Administration (FDA) and others are undergoing testing within phase 3 clinical trials
Summary
Cancer immunotherapy encompasses a number of different treatments aimed at stimulating the immune system in order to promote the recognition and the elimination of tumor cells [1]. Immune checkpoints inhibitors (ICIs) have emerged as anticancer agents able to modify, for the better, the natural history of a wide range of malignancies, such as melanoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), bladder cancers, Hodgkin lymphoma and others [2]. These agents have dramatically improved the prognosis of many cancer patients, they are critically associated with a broad spectrum of sometimes ill-defined adverse events, caused by the uncontrolled activation of the immune system, due to the lack of physiological brakes (i.e. the immune checkpoints themselves), referred to as immune-related adverse events (irAEs) characterized by clinical manifestations that closely resemble autoimmunity disorders [3, 4]. We will discuss the molecular pathways modulated by ICIs on Tcell activation, the proposed mechanisms of ICIs-related renal injury, with a particular focus on the development of AKI, as well as recent insights into clinical trials, and biomarkers studies aimed at assessing response to treatment
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