Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management

Abstract

Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis-treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy's transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies.

Keywords: ICI-related nephritis; acute kidney injury (AKI); auto-antibodies; auto-reactive T cells; biomarkers of ICI-AKI; drug-specific T cells; immune checkpoint inhibitors (ICI); management of ICI-AKI; nephritis as a predictor of treatment response; renal biopsy; renal complications.

Figure 1

(a) Schematic diagram depicting auto-reactive T cells and loss of self-tolerance to antigens. Self-reactive T cells that exit from the thymus are normally kept dormant through various mechanisms including CTLA-4 and PD-1 checkpoint signaling. Removal of checkpoint signaling in the context of ICI therapy may lead to the activation of self-reactive T cells and kidney damage; (b) Schematic diagram depicting checkpoint receptor expression on non-tumor tissue. PD-L1 is expressed at low levels on renal tubular cells and can be significantly upregulated by interferon treatment. Anti-PD-L1 antibodies can theoretically bind to these cells and cause renal injury; (c) Schematic diagram depicting reactivation of drug-specific T cells. Patients who are taking medications that can cause tubular injury (like PPIs, NSAIDs, or antibiotics) can directly or indirectly trigger an immune response by binding to tubular antigens and acting as haptens. These haptens can get trapped in the kidney tissue and lead to tubular damage. Auto-reactive T cells, which may be dormant initially, could become activated when ICIs are administered; (d) Schematic diagram depicting development of auto-antibodies. ICI administration could result in the production of auto-antibodies directed against antigens presented by TECs, mesangial cells, or podocytes.