Risk factors associated with immune checkpoint inhibitor–induced acute kidney injury compared with other immune-related adverse events: a case–control study

Abstract

Background Immune checkpoint inhibitors (ICIs) foster anti-cancer immune response. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affect various organs, including kidneys, mostly as acute tubule-interstitial nephritis, which pathophysiology remains unclear. We conducted a multicenter case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) to those of patients diagnosed with other IRAEs. Methods We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, 4 reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a p<0.05 were included as covariates in a multivariate analysis. Results Therefore, 167 ICI-AKI reports were compared to 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 vs 64.6 years, p = 0.0135). and chronic kidney disease was significantly more prevalent (12.0% vs 3.3%, p = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione (adjusted odds ratio [OR] 6.53; 95% confidence interval [CI] 2.21-19.31; p = 0.0007), a non-steroidal anti-inflammatory drug (NSAID, OR 3.18; 95%CI 1.07-9.4; p = 0.0368), or a proton-pump inhibitor (PPI, OR 2.18; 95%CI 1.42-3.34; p = 0.0004). Conclusion This study is limited by lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a “second-hit” that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).

‘Prevention is better than cure’: warning for comedications in patients receiving immune checkpoint inhibitors to avoid acute kidney injury

“…In this issue of Clinical Kidney Journal , Gerard et al. report risk factors associated with ICI-induced AKI by comparing ICI-treated patients with ICI-AKI versus ICI-treated patients with non-renal irAEs [ 3 ]. The findings are based on the examination of reports registered in the French Pharmacovigilance Database (PVD).…”

“…Clinical data were analysed as well as concomitant drugs known for their propensity to induce ATIN. A total of 167 reports of ICI-AKI were included and compared with 668 reports of extrarenal irAEs, according to a randomly assigned 4:1 ratio [ 3 ]. The most frequent malignancies were lung cancers and melanoma (as expected because both were the first cancers to benefit from ICI treatment).…”

“…A low proportion of patients (6%–7%) received a combination of ICI. The relative share of the different ICI was not significantly different between the two groups [ 3 ]. Among ICI-AKI reports, 74 (44.3%) patient files mentioned at least one concomitant extrarenal irAE, most frequent haematologic (7.2%), hepatobiliary (6.6%) and/or cutaneous (6%) irAE.…”

“…Time to onset for ICI-AKI was 2 months. The present study identified five factors that were significantly and independently associated with ICI-AKI in multivariate analyses: older age, previous chronic kidney disease (CKD) and concomitant use of fluindione [odds ratio (OR) 6.53], non-steroidal anti-inflammatory drug (NSAIDs, OR 3.2) and proton pump inhibitor (PPI, OR 2.2) [ 3 ]. This association between comedications and the development of ICI-AKI suggests that ICI may be a ‘second hit’ that precipitates AKI caused by a concomitant drug.…”

“…In the second study, three factors were identified: previous CKD defined by eGFR <59 mL/min/1.73 m 2 (OR 2.23), PPI use (OR 2.4) and prior or concomitant irAEs (OR 2.07) [ 5 ]. In contrast, the present study compares patients with ICI-AKI with ICI-treated patients with extrarenal irAEs, and is, therefore, able to identify specific renal irAE risk factors [ 3 ]. Its multicentric case–control design with a 4:1 ratio enables the inclusion of a large number of patients increasing statistical relevance.…”