Concomitant Proton Pump Inhibitors and Immune Checkpoint Inhibitors Increase Nephritis Frequency

Abstract

Background/Aim: Concomitant proton pump inhibitor (PPI) and immune checkpoint inhibitor (ICPI) were determined as risk factors of acute kidney injury. To identify the type of PPI associated with ICPI-induced nephritis, we used the Japanese Adverse Drug Event Report database. Patients and Methods: ICPIs (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, and avelumab) and PPIs (esomeprazole, omeprazole, vonoprazan, rabeprazole, and lansoprazole) were selected as suspected nephritis-inducing drugs. Results: The cases of concomitant use of atezolizumab and rabeprazole, ipilimumab and omeprazole, ipilimumab and lansoprazole, nivolumab and esomeprazole, nivolumab and omeprazole, nivolumab and rabeprazole, nivolumab and lansoprazole, pembrolizumab and esomeprazole, as well as pembrolizumab and lansoprazole had a significantly higher reported odds ratio than monotherapy cases. Conclusion: Male patients or patients using ICPIs and PPIs (excluded vonoprazan) concomitantly should be monitored for renal function after chemotherapy.Immune checkpoint inhibitors (ICPIs) are used as essential anti-cancer chemotherapy in various types of cancers (1-5). Blockade of programmed cell death-1 (PD-1)/PD-ligand-1 signaling (6, 7) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) signaling (8) activates T-cell mediated antitumor immunity; therefore, ICPIs exert dramatic effects in patients with cancer expressing these proteins. As ICPIs induce antitumor effects by reactivating antitumor immunity, they also cause immune-related adverse events (irAEs), such as interstitial pneumonia and nephritis (9-11), thyroid dysfunction (5, 9), type 1 diabetes mellitus (5), and lupus erythematosus (12). The clinical features and outcomes of ICPI-induced acute kidney injury (AKI) have been reported (13-15). As a pathological feature, acute tubulointerstitial nephritis was the primary pathologic lesion with lymphocyte infiltration. In addition, lower baseline estimated glomerular filtration rate (eGFR), use of proton pump inhibitor (PPI), and ICPI combination were determined as risk factors of ICPI-associated AKI (13). Furthermore, the mortality of patients with renal recovery after ICPI-induced nephritis was better than that of patients without renal recovery (16). To improve prognosis for patients treated with ICPIs, the prevention of ICPI-induced nephritis is essential.PPIs are traditionally widely used for the treatment of several acid-related disorders, including peptic ulcer disease, gastroesophageal reflux disease, and Helicobacter pylori eradication. Although the use of PPIs was perceived as safe, it is associated with the incidence of AKI (17-22). In particular, omeprazole is associated with acute interstitial nephritis (AIN) (17). Because AKI and AIN increase the risk of chronic kidney disease (CKD), the prevention of PPIinduced AIN could decrease the initiation of dialysis (23)(24)(25).Since the frequency of overall incidence of ICPI-induced AKI is 2.2% (26), the information regarding ICPI-induced AKI is limited. In a...

Adverse Renal Effects of Anticancer Immunotherapy: A Review

“…Their impact on AKI development in patients treated with ICIs was an object of interest in numerous studies. Apart from the research mentioned above, such an association was also documented in other studies [ 71 , 72 ]. Risk factors for the ICI-induced nephrotoxicity are shown in Table 2 .…”

Adverse Renal Effects of Anticancer Immunotherapy: A Review

“…Their impact on AKI development in patients treated with ICIs was an object of interest in numerous studies. Apart from the research mentioned above such an association was also documented in other studies [71,72]. AEs: adverse events, OR: odds ratio, CI: confidence interval, irAEs: immune-related adverse events, AKI: acute kidney injury, ACEI: angiotensin-converting-enzyme inhibitors, ARB: angiotensin receptor blockers, eGFR: estimated glomerular filtration rate, PPIs: proton pump inhibitors, Anti-CTLA-4: anti-cytotoxic T-lymphocyte-associated protein 4, Anti-PD1: anti-programmed cell death protein 1, Anti-PD-L1: antiprogrammed death-ligand 1.…”

Analyses of Ocular Adverse Reactions Associated With Anticancer Drugs Based on the Japanese Pharmacovigilance Database

“…Although the safety signals were evaluated by focusing on the suspect drugs, the influence of concomitantly administered drugs cannot be ruled out. Second, biases including under-or over-reporting and confounding caused by comorbidities cannot be ruled out in this large spontaneous reporting system (16,19). Third, the number of cases with OARs was small, especially for subgroup analysis.…”

“…The Japanese Adverse Drug Event Report (JADER) is a nationwide database of spontaneous reports of ADR published by the Pharmaceuticals and Medical Devices Agency (PMDA), a pharmaceutical regulatory authority in Japan. The calculation of reporting odds ratio (RORs) and information components (ICs) (15)(16)(17)(18) based on safety signal data from JADER allows for the investigation of anticancer drug-induced OARs.…”