Nephrotoxicity Of Immune Checkpoint Inhibitors: A Disproportionality Analysis From 2013 To 2020

Nephrotoxicity occasionally occurs during treatment with immune checkpoint inhibitors (ICIs). Few related studies compare the differences between these drugs. This study aimed to characterize nephrotoxicity after ICI initiation systematically. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis, including information components (ICs) and reporting odds ratios (RORs), was performed to determine the potential renal toxicity of ICIs. A total of 7,204 reports of renal adverse events (AEs) were identified in the FAERS database. were most commonly reported for nivolumab (46.84%). Strong signals were detected in male patients combined with ICIs. In the clinical application of ICIs, attention should be paid to patients, especially male patients, with acute kidney injury, nephritis, autoimmune nephritis, and other nephrotoxic AEs. The use of ICIs is likely to aggravate their condition. 

Keywords: adverse events; Adverse Event Reporting System; disproportionality analysis; immune checkpoint inhibitors; nephrotoxicity

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Introduction

Immune checkpoint inhibitors (ICIs) are a novel class of medications in the treatment of cancer. They have rapidly obtained popularity for their success in improving clinical outcomes in a great many cancer types (Wrangle et al. 2018). The immune checkpoints programmed cell death protein 1 pathway (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) acted as a "brake" role in immune function and suggested that immune checkpoint inhibition may reactivate T cells and eliminate cancer cells effectively (Ljunggren et al. 2018). 

Accumulating evidence indicates that the inhibition of PD-1 promotes an effective immune response against cancer cells (Messenheimer et al. 2017). In addition, the development of PD-L1 checkpoint inhibitors has changed the landscape of non-small-cell lung cancer (NSCLC) therapy, with 2 approvals from the US Food and Drug Administration (FDA) of PD-1 inhibitors for second-line therapy (Sacher and Gandhi 2016). About the clinical manifestations of CTLA-4, first-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level (Hellmann et al. 2019).

However, the risk of adverse events (AEs) of ICIs has attracted attention in clinical practice. Nephrotoxicity is one ubiquitous AE. It may induce serious and fatal events if doctors do not recognize and treat it promptly. Renal immune-related adverse events are rare, with an estimated incidence of 2% with anti-PD-1/PD-L1 and 5% with combination therapy in a review of published phase 2 and 3 trials, but more recent studies have suggested that the incidence of acute kidney injury is higher than that initially reported (Li et al. 2021).

In this study, a disproportionality analysis was conducted to characterize and evaluate nephrotoxicity associated with ICI regimens using AE data in the FDA Adverse Event Reporting System (FAERS) database. Although the data in the FAERS database may lack detailed clinical information, this approach may help discover potential drug-toxicity associations.

Materials and Methods

Study design and data sources 

This retrospective, pharmacovigilance study is a disproportionality analysis based on the FAERS database, a collection of reports of AEs by consumers, healthcare providers, drug manufacturers, and others. It allows for the signal detection and quantification of the association between drugs and the reports of AEs (Min et al. 2018). Input data for this study were taken from the public release of the FAERS database, covering the period from the first quarter of 2013 to the second quarter of 2020.

Procedure 

The drugs studied included antibodies targeting PD-1 (nivolumab and pembrolizumab), PD-L1 (atezolizumab, nivolumab, and durvalumab), and CTLA-4 (ipilimumab and tremelimumab). Generic names and brand names were used to identify the records associated with the ICIs because there is no uniform coding system for medications.

This study included all renal disorders (excluding nephropathies) (Medical Dictionary for Regulatory Activities (MedDRA) code 10038430) and all nephropathies (MedDRA code 10029149) according to MedDRA version 23.0. In the FAERS database, each report is coded using the preferred terms (PTs) from MedDRA, the international medical terminology developed by the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Statistical analysis 

Disproportionality appears when a drug is associated with a specific AE in pharmacovigilance studies. Two-by-two contingency tables were used to count the AE reports of the suspected drugs and other drugs (Table 1). Two data mining methods, reporting odds ratios (RORs) and Bayesian confidence propagation neural networks (BCPNNs) of information components (ICs), were used to calculate disproportionality.

The ROR can be expressed as (Stricker and Tijssen 1992) 

The standard error of ln (ROR) and 95% confidence interval can be calculated by

The BCPNN and its variance can be calculated as (Weinstein et al. 2009)

and γij = 1, αi = 1, α = 2, βj = 1, and β = 2; C is the total number of reports in the database, Cij is the number of combinations between the ICI drugs (i) and the nephrotoxicity reaction (j), Ci is the total number of reports on the ICI drugs (i) in the database and Cj is the total number of reports on the nephrotoxicity reaction (j) in the database. The signal was considered significant if the lower limit of the 95% confidence interval (ROR025) was higher than 1, or if the lower end of the 95% confidence interval of the information component (IC025) was greater than 0. All analyses were performed with SAS version 9.4 and R version 3.6.3. Ethics approval and consent to participate are not applicable.

Results 

Descriptive analysis

A total of 52,583,692 records from the FAERS database were involved in this study, and 7,204 reports were AEs of nephrotoxicity after treatment with ICIs. The clinical characteristics of patients with kidney toxicity using ICIs are shown in Tables 2 and 3. Among all reports of nephrotoxicity associated with ICIs, the proportion of males was larger than that of females (63.66% vs. 29.96%). With further analysis, the signal was also detected (ROR025 = 2.32, IC025 = 0.49). Among all reports of nephrotoxicity associated with each ICI, the signal of males was larger than that of females (Table 4). Significant differences existed between different age groups, too. The proportion of the elderly (> 65) was larger than that of the non-elderly (< 65) (51.94% vs. 33.94%), and the difference was significant (ROR025 = 1.12, IC025 = 0.04), which might be attributed to the degenerative change of the elderly. The most frequently reported severe outcomes were other serious medical events and hospitalization. Hospitalization (ROR025 = 2.18, IC025 = 0.79), death (ROR025 = 1.50, IC025 = 0.53), and life-threatening (ROR025 = 2.08, IC025 = 1.01) events associated with renal AEs after ICI treatment were reported, indicating the potentially life-threatening nature of ICI-related nephrotoxicity

Table 2 shows the clinical characteristics of patients with kidney toxicity using ICIs and any other drugs. The number and the percentage are shown. *Missing value in FAERS database. AEs, adverse events; IC025, the lower end of the 95% confidence interval of IC; ROR025, the lower limit of the 95% confidence interval of ROR; Empty cells; there is not enough data to compute.

However, differences in various specific nephrotoxic AEs were observed in all ICI regimens. Among all the reports of AEs of nephrotoxicity, acute kidney injury (2,404, 33.37%), renal failure (1,128, 15.66%), renal impairment (778, 10.8%), tubulointerstitial nephritis (617, 8.56%), nephritis (350, 4.86%), and renal disorder (299, 4.15%) were the most frequently reported (Table 5). These reports account for 77.47% of all the reports. The other reports of AEs of nephrotoxicity are considered rare.

The spectrum of nephrotoxicity AEs differs in immunotherapy regimens 

In general, ICIs were hardly associated with renal AEs. When further analysis was done, there was a significant difference between AEs related to nephrotoxicity and atezolizumab in total (IC025: 0.05; ROR025: 1.04), but not the other ICIs (Table 6). Eleven preferred terms (PTs) were significantly associated with atezolizumab treatment, ranging from pyelonephritis (ROR025 = 1.20, IC025 = 0.07) to glomerulonephritis chronic (ROR025 = 51.95, IC025 = 1.17). Nivolumab was with the broadest spectrum of renal AEs with 26 PTs detected as signals, ranging from anuria (ROR025 = 1.02, IC025 = −0.03) to autoimmune nephritis (ROR025 = 29.03, IC025 = 3.46). Twenty-one PTs were significantly associated with pembrolizumab treatment, ranging from renal tubular necrosis (ROR025 = 1.06, IC025 = 0.04) to immune-mediated renal disorder (ROR025 = 185.22, IC025 = 1.69). Nine PTs were significantly associated with ipilimumab treatment, ranging from nephrotic syndrome (ROR025 = 1.08, IC025 = −0.04) to autoimmune nephritis (ROR025 = 72.67, IC025 = 3.77). For durvalumab, 7 disproportionality signals were detected, ranging from biotic microangiopathy (ROR025= 1.97, IC025 = 0.77) to autoimmune nephritis (ROR025 = 18.27, IC025 = 0.72). A small number of the other signals were reported. But some very strong signals were found. Avelumab was much stronger associated with pyelonephritis (ROR025 = 5.27, IC025 = 1.17). Cemiplimab was much stronger associated with autoimmune nephritis (ROR025 = 375.35, IC025 = 0.83) and kidney transplant rejection (ROR025 = 13.22, IC025 = 0.20). Tremelimumab was much stronger associated with nephritis (ROR025 = 27.90, IC025 = 2.83), etc (Figs. 1 and 2).