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

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and outcomes, leading to an expanding use in millions of patients worldwide. However, they can cause a spectrum of immune-related adverse events (irAEs). Essentially, any organs can be affected by irAEs, which has emerged as therapy-limiting side effects. In the kidneys, ICI-associated acute interstitial nephritis (ICI-AIN) leads to acute kidney injury (AKI) in 2–5% of patients on ICI therapy. AKI associated with ICI therapy pathologically presents with AIN in nearly 90% of the cases, but the pathophysiology of ICI-AIN remains to be defined. The generation of autoreactive T cells in patients receiving AIN-inducible drugs, such as proton pump inhibitors (PPIs), is one of the leading theories, supported by a higher incidence of ICI-AIN in patients on these AIN-inducible drugs. In this review, we will discuss our understanding of the incidence, potential pathophysiological mechanisms, clinical presentations, risk factors, diagnosis, and management of PPI-related AIN and its interaction with ICI therapy.

Proton pump inhibitors and the risk of acute kidney injury in cancer patients receiving immune checkpoint inhibitors: A Danish population‐based cohort study

“…In line with these results, Seethapathy et al showed in a cohort study that PPI use at ICI initiation was associated with an adjusted HR of 2.85 6 . Since both ICIs and PPIs are drugs associated with acute interstitial nephritis, 19,30 PPIs are hypothesized to predispose to acute interstitial nephritis in patients receiving ICI by activating or reactivating drug‐specific T‐cell‐mediated immune reactions 19,20,31 . The results from previous studies finding an association between PPI and AKI in patients receiving ICI are in line with the crude results from our per‐protocol analysis but in contrast to the weighted results from our analyses.…”

Proton pump inhibitors and adverse kidney outcomes during immune checkpoint blockade: time to sound the alarm?

“…In this issue of Clinical Kidney Journal , Miao et al. [ 4 ] review and summarise the evidence evaluating the link between PPIs and ICIs in the development of AIN and revisit the role of PPIs in adverse kidney outcomes. Growing evidence from observational studies appears to suggest a potential association between PPIs and ICI-associated AIN (ICI-AIN), evidenced by an increased risk of ICI-related acute kidney injury (AKI) [ 5–8 ] as well as a more rapid onset of AKI [ 9 ] in patients concurrently on PPIs and ICIs.…”

“…Miao et al. [ 4 ] reviewed and found few clinical or histological features that reliably distinguish between classic AIN induced by non-steroidal anti-inflammatory drugs (NSAIDs) and/or antibiotics, PPI-AIN and ICI-AIN, perhaps owing to the non-specific clinical presentation of AIN in general. Of note, perceived differences relating to the timing of onset of AKI in relation to drug exposure has been described among classic AIN, PPI-AIN and ICI-AIN [ 16 ], but overlap appears to exist.…”

“…However, there remains a paucity of data guiding the safety and use of other AIN-predisposing medications in the setting of ICI-AIN, with trimethoprim–sulfamethoxazole being a drug of particular relevance, being the most common option for Pneumocystis carinii pneumonia prophylaxis during prolonged steroid therapy. Its avoidance has been suggested in this specific setting [ 4 ] on the basis of AIN-risk minimisation in general rather than a recommendation rooted in evidence.…”

“…The epidemiological evidence presented in the review by Miao et al. [ 4 ] signals yet another potential association of PPIs with adverse kidney outcomes, with emerging data from a specific population of cancer patients receiving ICIs. Prospective studies are warranted to delineate the true relationship of ICIs and PPIs in the development of AIN, but careful and appropriate use of PPI in ICI-treated patients should be strongly encouraged on the basis of precautionary principles.…”