Nephrotoxicity Associated With Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) that target cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death receptor 1 (PD-1) are having a marked impact on the care of patients with advanced melanoma, lung cancer, urothelial cancers, and kidney cancers, among others.1

Despite clinical benefits, ICI therapy may be associated with distinct immune-related adverse events (irAEs), including dermatologic, gastrointestinal, hepatic, and endocrine.1 Acute kidney injury (AKI) is a rare but potentially serious complication of ICIs.1 The incidence of ICI-related AKI is around 2 – 5%,2 with acute tubulointerstitial nephritis (AIN) being the most common pathology.2

Risk factors for ICI-induced AKI include a low baseline estimated glomerular filtration rate (eGFR), concurrent use of proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs, and a concurrent or recent ICI-induced event, such as a rash or colitis.2 The median onset of ICI-induced AKI is 12 weeks post ICI initiation, and a kidney biopsy may be required to differentiate between nephrotoxicity associated with traditional chemotherapy and ICI-induced AKI.2 Although all ICIs can cause renal side effects, the combination of CTLA-4 and PD-1 inhibitors carries a higher risk of ICI-induced AKI (~ 5%).2

There are no validated biomarkers for the diagnosis of ICI-induced AKI, so a kidney biopsy is the gold standard.2 In the absence of a biopsy, probable ICI-induced AKI is diagnosed by an increase in creatinine ≥50% on at least two consecutive values and the absence of an alternative etiology, along with sterile pyuria (≥5 white blood cells/high-power field [hpf] on microscopy) and/or an associated extrarenal irAE.3 A nephrology consult is indicated when the creatinine is 2 – 3 times above baseline, prior to which the ICI is held while considering alternative causes (e.g. recent IV contrast, medications, fluid status, and urinary tract infection [UTI]).3

The goal of managing ICI-related AKI is to prevent kidney failure without denying beneficial cancer treatment, as summarized in the ASCO guidelines.3 For patients with grade 2 AKI (creatinine 2 – 3 times above baseline), holding the ICI and treating with steroids (0.5 – 1 mg/kg/day prednisone) are indicated if other etiologies are ruled out, with steroid tapering if renal function improves to grade 1 AKI (creatinine 1.5 – 2.0 times above baseline).3 Studies have shown that roughly 85% of patients with ICI-induced AKI who received steroids have full or partial remission, and for these patients rechallenging with ICI therapy is a reasonable strategy.1 In one observational study, among the subset of patients who were rechallenged with ICI therapy, approximately 84% did not develop recurrent ICI-associated AKI.4 The incidence of ICI-associated AKI is likely to increase as ICI use expands; thus, collaboration between the nephrology and oncology communities is key to optimizing care and quality of life for these cancer patients.

Postow M. Toxicities associated with checkpoint inhibitor immunotherapy. In: UpToDate, Post TW (Ed); UpToDate, Waltham, MA (Last accessed: April 6, 2022.)
Seethapathy H, Herrmann S, Sise ME. Kidney Med. 2021;3(6):1074-1081.
Schneider BJ, et al. J Clin Oncol. 2021;39(36):4073-4126.
Gupta S, et al. J Immunother Cancer. 2021;9(10):e003467.