Risk factors of immune checkpoint inhibitor-associated acute kidney injury: evidence from clinical studies and FDA pharmacovigilance database

Abstract

Background Several risk factors of immune checkpoint inhibitors (ICIs)-associated acute kidney injury (AKI) have been reported sporadically. To identify the risk factors of ICIs-associated AKI in a large-scale population, therefore we conducted a systematic review and a real-world retrospective study. Methods We search literature concerning risk factors of ICIs-associated AKI in ClinicalTrials.gov and electronic databases (PubMed, Cochrane Library, Embase) up to January 2022. Meta-analysis was performed by using odds ratios (ORs) with 95%CIs. In a separate retrospective pharmacovigilance study by extracting data from US FDA Adverse Event Reporting System (FAERS) database, disproportionality was analyzed using the reporting odds ratio (ROR). Results A total of 9 studies (5927 patients) were included in the meta-analysis. The following factors were associated with increased risk of ICIs-associated AKI, including proton pump inhibitors(PPIs) (OR = 2.07, 95%CI 1.78–2.42), angiotensin-converting enzyme inhibitors (ACEIs)/ angiotensin receptor blockers (ARBs) (OR = 1.56, 95%CI 1.24–1.95), nonsteroidal anti-inflammatory drugs (NSAIDs) (OR = 1.29, 95%CI 1.01–1.65), diuretics (OR = 2.00, 95%CI 1.38–2.89), diabetes mellitus (OR = 1.28, 95%CI 1.04–1.57), genitourinary cancer (OR = 1.46, 95%CI 1.15–1.85), combination therapy of ICIs (OR = 1.93, 95%CI 1.25–2.97) and extrarenal immune-related adverse events(irAEs) (OR = 2.51, 95%CI 1.96–3.20). Furthermore, analysis from FAERS database verified that concurrent exposures of PPIs (ROR = 2.10, 95%CI 1.91–2.31), ACEIs/ARBs (ROR = 3.25, 95%CI 2.95–3.57), NSAIDs (ROR = 3.06, 95%CI 2.81–3.32) or diuretics (ROR = 2.82, 95%CI 2.50–3.19) were observed significant signals associated with AKI in ICIs-treated patients. Conclusions Concurrent exposures of PPIs, ACEIs/ARBs, NSAIDs or diuretics, diabetes mellitus, genitourinary cancer, combination therapy, and extrarenal irAEs seem to increase the risk of AKI in ICIs-treated patients.

Development and validation of a nomogram for predicting the occurrence of renal dysfunction after treatment of immune checkpoint inhibitor: a retrospective case–control study

“… 12 However, hypertension was not demonstrated to be associated with ICIs-related AKI depending on our previous result of systemic review. 5 On the other hand, hypertension was a well-known risk factor to induce kidney injury or accelerate the decline of eGFR in CKD. In our study, comorbidity of hypertension was revealed to be an independent predictor of renal dysfunction in ICIs-treated patients with cancer.…”

“… 2–4 Several risk factors of ICIs-related AKI were reviewed in our previous study, including concurrent exposures to proton pump inhibitor (PPI), ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB), non-steroidal anti-inflammatory drug (NSAID) or diuretic, comorbidity of diabetes mellitus, primary cancer of genitourinary system, ICIs combination therapy and extrarenal irAEs. 5 Recovery of kidney function was observed in only 40%–45% of these AKI patients. 6 7 Though the relationship between ICIs-related AKI and the mortality of patients with cancer was still controversial, 3 8–13 patients with persistent renal dysfunction following ICIs-related AKI (non-recovery) were found to be at a higher risk of all-cause mortality.…”

Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management

“…The use of PPIs also showed a potential link [ 18 , 19 ], although cautious interpretation is necessary due to the lack of evidence from randomized controlled trials, as confounding factors might influence the results. Malignancies and ICI classes: Genitourinary cancers were associated with a higher AKI risk in ICI-treated patients, whereas lung cancer and melanoma demonstrated varying risks [ 20 ]. It is essential to acknowledge that these data encompassed both ICI-AKI and non-ICI-AKI cases.…”

“…None of the ICI categories (anti-PD-1, anti-PD-L1, or anti-CTLA-4) showed a distinct propensity for AKI. However, combining anti-PD-1/PD-L1 with anti-CTLA-4 significantly correlated with AKI [ 18 , 20 ]. Chemotherapy: Limited data exist regarding patients with prior chemotherapy exposure as a risk factor for AKI.…”

“…Malignancies and ICI classes: Genitourinary cancers were associated with a higher AKI risk in ICI-treated patients, whereas lung cancer and melanoma demonstrated varying risks [ 20 ]. It is essential to acknowledge that these data encompassed both ICI-AKI and non-ICI-AKI cases.…”