Immune Checkpoint Inhibitor Nephrotoxicity: Update 2020

Abstract

Immune checkpoint inhibitors (ICPIs) have transformed the landscape of oncology, but are associated with a variety of autoimmune adverse events, including AKI. ICPI-associated AKI (ICPI-AKI) is emerging as an increasingly frequent cause of AKI in patients with cancer, and poses unique diagnostic and management challenges to clinicians who care for these patients. In this review, we describe the incidence and risk factors for ICPI-AKI, including proton pump inhibitor use, CKD, and combination immunotherapy. We discuss the limitations of the various definitions used for ICPI-AKI in prior studies, and propose a novel classification system (definite, probable, and possible ICPI-AKI) that recognizes the diagnostic uncertainty inherent in many cases. We discuss the key clinicopathologic features and treatment strategies for ICPI-AKI, including the role of kidney biopsy versus empirical treatment with steroids. We also explore the under-studied area of ICPI use in the setting of solid organ transplantation, where nephrologists and oncologists must balance the risk of rejection versus treating the underlying malignancy. Finally, we summarize existing data on the role of ICPI rechallenge after an episode of ICPI-AKI.

Keywords: Acute Kidney Injury and ICU Nephrology; Acute kidney injury; Clinical Nephrology; Nephro-Pharmacology; acute interstitial nephritis; acute tubulointerstitial nephritis; immune-related adverse event; immunotherapy.

Figure 1.

PPI use lower baseline eGFR and combination treatment with anti–CTLA-4 and anti–PD-1/PD-L1 agents are independently associated with ICPI-AKI. Combined therapy refers to combination therapy with a cytotoxic T lymphocyte–associated protein 4 inhibitor and a programmed cell death protein 1 (PD-1)/PD-ligand 1 inhibitor. Ipilimumab/nivolumab was the combination therapy regimen in 75% of cases and 66% of controls. CKD was defined as a baseline (pretreatment) eGFR <60 ml/min per 1.73 m². P values were calculated with the chi-squared test. Data from Cortazar et al. (21). PPI, proton pump inhibitor.

Figure 2.

Evaluation and treatment algorithm for suspected immune checkpoint inhibitor–associated AKI. Stages 1, 2, and 3 AKI are based on the Kidney Disease: Improving Global Outcomes AKI staging definition (19). *Clinical review of risk factors (e.g., prior or concomitant PPI use, prior or concomitant extrarenal irAEs). **Contraindications to kidney biopsy include solitary kidney, anticoagulation use that cannot be safely discontinued, or uncontrolled hypertension. ATI, acute tubular injury; ATIN, acute tubulointerstitial nephritis; ICPI, immune checkpoint inhibitor; irAE, immune-related adverse event.

Figure 3.

Incidence of solid organ transplant rejection may be higher after anti–PD-1 therapy. Data are derived from published case series and case reports of rejection after immune checkpoint inhibitors. CTLA-4, cytotoxic T lymphocyte–associated protein 4; PD-1, programmed cell death protein 1; PD-L1, PD-ligand 1.