Immunotherapy in oncology and the kidneys: a clinical review of the evaluation and management of kidney immune-related adverse events

Abstract

Immune checkpoint inhibitors (ICI) are now widely used in the treatment of many cancers, and currently represent the standard of care for multiple malignancies. These agents enhance the T cell immune response to target cancer tissues, and have demonstrated considerable benefits for cancer outcomes. However, despite these improved outcomes, there are important kidney immune-related adverse events (iRAEs) associated with ICI. Acute tubulo-interstitial nephritis remains the most frequent kidney iRAE, however glomerular lesions and electrolytes disturbances are increasingly being recognized and reported. In this review, we summarize clinical features and identify risk factors for kidney iRAEs, and discuss the current understanding of pathophysiologic mechanisms. We highlight the evidence basis for guideline-recommended management of ICI-related kidney injury as well as gaps in current knowledge. We advocate for judicious use of kidney biopsy to identify ICI-associated kidney injury, and early use of corticosteroid treatment where appropriate. Selected patients may also be candidates for re-challenge with ICI therapy after a kidney iRAE, in view of current data on recurrent rates of kidney injury. Risk of benefits of re-challenge must be considered on an individual considering patient preferences and prognosis. Lastly, we review current knowledge of ICI use in the setting of patients with end-stage kidney disease, including kidney transplant recipients and those receiving dialysis, which suggest that these patients should not be summarily excluded from the potential benefits of these cancer therapies.

Keywords: AKI; cancer; glomerulonephritis; immune checkpoint inhibitors; nephrotoxicity.

Figure 1:

In the normal physiology, quiescent CD8+ T lymphocytes become activated when antigen presenting cells (APCs) present major histocompatibility complex–bound antigen fragments to T cell receptors. The secondary activation/co-stimulatory signals (involving CD80/86 and CD28) generate effective immune response. CTLA4 receptors on the inactive T cells inhibit the activation process binding to the CD80/86 complex on the APCs resulting in T cell anergy. Monoclonal antibodies (Mabs) against CTLA4 (ipilimumab/tremelimumab) remove the inhibitory signal facilitating the activation of CD8+ T cells. In the tumor micro-environment, the cancer cells evade the T cell response by increased expression of ligands (eg.PD-L1) which bind to immune checkpoints (eg. PD-1) on the T cells preventing the immune response. This immune tolerance by the cancer cells is inhibited by the Mabs against PD-1 (pembrolizumab/nivolumab) and PD-L1 (atezolizumab/avelumab). In the presence of ICI, T cells can lose their tolerance against normal renal tubular epithelium leading on to kidney injury.

Figure 2:

Potential mechanisms of kidney injury in patients treated with ICI.

Figure 3:

Spectrum of kidney diseases associated with ICI.