Immune checkpoint inhibitor related nephrotoxicity: Advances in clinicopathologic features, noninvasive approaches, and therapeutic strategy and rechallenge

Abstract

Immune checkpoint inhibitors (ICIs) are used increasingly to treat more than 17 cancers and have shown promising therapeutic results. However, ICI use can result in a variety of immune-related adverse events (IRAEs) which can occur in any organ, including the kidneys. Acute kidney injury (AKI) is the most common nephrotoxicity, classically related to acute interstitial nephritis. Much more diverse patterns and presentations of ICI-related kidney injury can occur, and have implications for diagnostic and therapeutic management approaches. In this review, we summarize the recently approved ICIs for cancer, the incidence and risk factors for nephrotoxicity, our current understanding of the pathophysiological mechanisms and the key clinicopathological features of ICI-related AKI, and therapeutic strategies. We also explore important knowledge that require further investigation, such as the risks/benefits of ICI rechallenge in patients who recover from an episode of ICI-related AKI, and the application of liquid biopsy and microbiome to identify noninvasive biomarkers to diagnose and predict kidney injury and guide ICI therapy.

Immune checkpoint inhibitors and their interaction with proton pump inhibitors–related interstitial nephritis

“…Acute interstitial nephritis (AIN) is the most common type of renal irAE, being found in 80%–90% of patients who undergo kidney biopsy [ 7 , 8 ]. Several risk factors have been identified in patients with ICI-associated AIN (ICI-AIN), including use of drugs such as proton pump inhibitors (PPIs) [ 9 ]. Gastrointestinal symptoms, such as “heartburn” or “stomach discomfort”’ frequently caused by gastroesophageal reflux (GERD), are much more common in cancer patients.…”

“…Other manifestations of ICI-related renal irAEs, such as electrolyte abnormalities (e.g. hyponatremia, hypokalemia, hyperkalemia, hypophosphatemia, and hypomagnesemia) and renal tubular acidosis also have been reported [ 4 , 9 , 25 ].…”

“…Currently, there is no precise data demonstrating prevalence and incidence of ICI-AIN and PPI-related AIN (PPI-AIN). Available data indicated that the incidence of AKI in patients receiving ICIs was ∼17% [ 4 , 9 , 43–45 ]. However, the incidence of AKI directly related to ICI use was low, ranging from 0.8% to 5% [ 4 , 7 , 36 , 46 ].…”

“…AIN is the most common histopathological finding in ICI-AKI. However, other patterns that occur either alone or in conjunction with AIN also have been described, including various glomerular diseases and acute tubular injury or acute tubular necrosis though with a low incidence of <10% of all cases [ 9 ]. Glomerular diseases reported in ICI-AKI have pauci-immune crescentic glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, IgA and membranous nephropathy, and amyloid A amyloidosis [ 7 , 8 , 65 ].…”

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations

“…The most common is hyponatremia, generally secondary to ICI-related endocrinopathies or renal tubular damage. Hypokalemia and metabolic acidosis may indicate distal tubular damage [150,153].…”