Cardiorenal complications of immune checkpoint inhibitors

The development of immune checkpoint inhibitors (ICIs) has driven a revolutionary change in cancer treatment. Although traditional chemotherapeutic agents remain the first-line option for most cancers, targeted immune therapies are emerging as standard treatments for advanced-stage cancers. These agents target cell surface checkpoint proteins to stimulate the recognition and destruction of cancer cells by the immune system. Clinical studies have demonstrated these immunotherapeutics to elicit favourable antitumour responses in a variety of chemotherapy-refractory malignancies. However, use of these agents can also induce immune-related adverse events (irAEs) in off-target organs, including the heart and kidney. The most common manifestations of heart and kidney damage are myocarditis and acute interstitial nephritis, respectively, but other manifestations have been reported and, although rare, these off-target effects can be life threatening. Available data suggest that ICIs induce their off-target effects through several mechanisms, including direct binding to cell surface proteins expressed in healthy tissue, activation of T cells that cross-react with off-target tissues, generation of autoantibodies or by increasing levels of pro-inflammatory cytokines. Greater understanding of the adverse effects of cancer immunotherapies and the underlying mechanisms will facilitate the development of biomarkers to identify at-risk patients and approaches to prevent these irAEs. Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in cancer therapy; however, these agents can induce immune-related adverse events (irAEs) in off-target organs. This Review describes the mechanism of action of ICI therapies and how these agents induce irAEs in the kidney and heart. Key points Tumours use immune checkpoint pathways including programmed cell death protein 1 (PD-1)-mediated and cytotoxic T lymphocyte antigen 4 (CTLA4)-mediated pathways to evade recognition and destruction by the host immune system. Immune checkpoint inhibitors (ICIs) target these checkpoint pathways and re-programme the host immune system to activate an antitumour immune response. The use of ICIs is rapidly expanding for a variety of cancers owing to their established clinical efficacy; however, they are associated with a variety of immune-mediated injuries in different organs, including the kidney and heart. Immune-mediated kidney injury with ICIs most commonly manifests as acute interstitial nep