Kidney Complications of Immune Checkpoint Inhibitors: A Review

Abstract

Immunologic control of malignancy has long been recognized as an important determinant of disease progression. Recent advances in immunology have led to the focus on several mechanisms that can be targeted to achieve tumor suppression. In particular, checkpoint inhibition has evolved in less than a decade to become one of the most important strategies in cancer therapy, with a meaningful improvement in patient survival. Six agents have been approved for clinical use to date and many more are in the industry pipeline. The spectrum of malignancies responsive to immunotherapy ranges from advanced melanoma, for which the first immune checkpoint inhibitor ipilimumab was approved, to Hodgkin lymphoma, non-small cell lung cancer, renal cell carcinoma, and others. Notwithstanding its clinical benefits, checkpoint inhibition carries a risk for significant off-target toxicity stemming from the immune system activation. In this review, we discuss general principles of checkpoint inhibition, mechanisms of toxicity, and kidney complications of the treatment and propose diagnostic and treatment strategies when kidney injury occurs.

Keywords: Acute kidney injury (AKI); cancer immunotherapy; checkpoint inhibitor; corticosteroids; cytotoxic T-lymphocyte associated protein 4 inhibitor; immune-related adverse effect (irAE); immunotherapy; interstitial nephritis; onconephrology; programmed cell death protein 1 inhibitor; renal function; review.

Figure 1.

Kidney Biopsy of the Patient with Acute Kidney Injury while undergoing treatment with PD-1 checkpoint inhibitor. Legend: Light microscopy Panel A-low power, Panel B-higher power. H&E stain showing severe acute interstitial nephritis with tubulitis accompanied by acute tubular injury (images courtesy of Dr. Surya V. Seshan).

Figure 1.

Kidney Biopsy of the Patient with Acute Kidney Injury while undergoing treatment with PD-1 checkpoint inhibitor. Legend: Light microscopy Panel A-low power, Panel B-higher power. H&E stain showing severe acute interstitial nephritis with tubulitis accompanied by acute tubular injury (images courtesy of Dr. Surya V. Seshan).

Figure 2.

Schematic representation of T cell activation regulated by checkpoint inhibition with three hypothetical mechanisms of acute tubulointerstitial nephritis. Legend: Antigen carried by the antigen presenting cell (APC) activates a T cell receptor (TCR) with intracellular signal transduction by CD3 resulting in T cell proliferation, survival, and differentiation. This signal also stimulates the expression of CTLA-4 , which competes for binding CD80/86 with CD28, the costimulatory protein required for T cell activation, thereby leading to T cell anergy. PD-L1 is variably expressed by many native and tumor cells. By binding to PD-1 on a T cell, it suppresses its activation and promotes immunotolerance leading to T cell exhaustion. A T cell can be activated peripherally by an immunogenic checkpoint inhibitor (a), an immunogenic metabolite presented by the tubuloepithelial cells (b) or exhibit lesser immunotolerance for native kidney antigen (c).