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

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. 

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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 phonephrenitis (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).

Discussion 

Statistical analyses are useful tools 

Table 6 shows the information on total and specific ICI count in 2*2 contingency tables and calculation results by disproportionality analysis. The font will be bold if ROR025 is higher than 1 or IC025 is higher than 0. (a) The number of records with kidney AEs reported for ICIs. (b) The number of records with any other AEs reported for ICIs. (c) The number of records with any kidney AEs for other drugs. (d) The number of records reported other AEs for other drugs. ROR, reporting odds ratio; ROR025, the lower end of the 95% confidence interval of ROR; IC, information component; IC025, the lower end of the 95% confidence interval of IC.

in aiding signal detection in spontaneous reporting systems. In a previous study, the ROR was selected as the improper nationality analysis algorithm to characterize the spectrum, frequency, and clinical features of ICI-related adverse events (Raschi et al. 2019). However, no individual approach to detect signals is adequate and the concurrent use of other methods is essential (van Puijenbroek et al. 2002). Therefore, two methods, ROR and BCPNN, are used in this study. The selection of time intervals needs to pay attention to. In a previous study, disproportionality and Bayesian analysis were used in data mining to screen the suspected renal adverse effects after the administration of different ICIs, based on FAERS from January 2004 to September 2019 (Chen et al. 2020). However, the ICI's relatively larger market, ipilimumab, was listed in 2011. Redundant data increases the analysis results in probability errors. Our study is a pharmacovigilance study on ICI-associated neph toxicities based on more than 50 million records in the appropriate period. This makes our conclusion more stable compared with those of other studies.

Most clinical trials of ICIs have assessed clinical effects other than AEs and are only given a short brief description of these severe or even fatal AEs. To the best of our knowledge, this study is the most systematic and comprehensive collection until recently to compare the associations of renal adverse effects after different ICIs in real-world practice based on the FAERS pharmacovigilance database. Previous researches show that ICIs can increase the risk of organ system toxicities such as endocrine, hematological, ear, and labyrinth toxicity (Zhai et al. 2019; Hu et al. 2020; Ye et al. 2020). Nephrotoxicity is rare. Accounting for 2.47% among all ICI records with the latest data from January 1, 2013, to June 30, 2020.

Nephrotoxicity based on sex 

Notably, compared with male patients, nephrotoxic AEs were reported more than those reported among female patients (63.66% vs. 29.96%). The result reflects that males are a high-risk population for nephrotoxic AEs after treatment with ICI drugs. Previous research has also confirmed this (Chen et al. 2020). The reason for the difference in the occurring frequency of nephrotoxicity between males and females may be related to the level of sex hormones. Male hormones exert a deleterious effect in terms of increasing oxidative stress, activating the renin-angiotensin system, and worsening fibrosis within the damaged kidney, but female hormones exert a renoprotective effect (Valdivielso et al. 2019). Therefore, the clinical application of ICI drugs should focus on the occurrence of nephrotoxicity in male patients.

Association of total nephrotoxicity in total ICI use

The kidney is a vital organ for urine production, regulation of electrolytes and water, and the homeostasis of nutrients and metabolites in the body (Liu et al. 2019). Medications are a relatively common cause of kidney injury (Markowitz and Perazella 2005; Perazella 2005, 2009, 2012; Uchino et al. 2007; Izzedine et al. 2009; Moffett and Goldstein 2011; Hoste et al. 2015). Drug-induced nephrotoxicity is more common in hospitalized patients, particularly intensive care unit patients (Mehta et al. 2004; Uchino et al. 2007; Moffett and Goldstein 2011; Hoste et al. 2015), and is affected by the inherent nephrotoxic potential of the drug, underlying patient characteristics that enhance the risk for kidney injury, and the metabolism and excretion of the potentially offending agent by the kidney (Perazella 2003, 2005, 2009; Markowitz and Perazella 2005). The control group may express a higher proportion of renal toxicity. Also, ICI records may express too many other organ system toxicities, which may result in the expression of no significant association between renal AEs and ICIs.

Nephrotoxicity and atezolizumab 

The kidney is composed of glomeruli and tubules. No tendency of toxicity of each part is apparent in the atezolizumab group (Table 7), which might be attributed to the mechanism of this drug. Atezolizumab is an engineered humanized monoclonal IgG1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7.1 while it is sparing the interaction between PD-L2 and PD-1. To some degree, atezolizumab may have a higher appetency of the PD-L1 receptors that are scattered over the kidney, which should be confirmed by more empirical studies.

Proven nephrotoxicity and ICIs 

The results show that acute kidney injury, IgA nephropathy, and nephritis show a significant difference with partial ICIs, and some of these signals were stronger than others (Fig. 2). This may be related to the mechanism of the ICIs. CTLA-4 is a part of the B7:CD28 immunoglobulin family found on the surface of T-cells and transmits an inhibitory signal to the T-cell. PD-1 is expressed on T-cells and binds to its ligands PD-L1 and PD-L2 which are expressed in cancer cells and other immune cells. Antibodies against PD-1, such as nivolumab, pembrolizumab, and palivizumab, or PD-L1, such as MEDI4736 and MPDL3280A increase the anti-tumor T-cell response by blocking the interaction of PD1 and PD-L1 to prevent T-cell inactivation (Curran et al. 2010). Acute kidney injury, IgA nephropathy, and nephritis are complex diseases with many subtypes, and there are many causes of the disease (Cortazar et al. 2016; Mamlouk et al. 2019). Previous research has not been able to elaborate on the pathological mechanism. But what is certain is that changes in the immune system will affect other tissues, which is in line with the characteristics of the human body 

Autoimmune nephritis and ICIs 

The results show that autoimmune nephritis and a variety of drugs are related, including atezolizumab (ROR025 = 20.97, IC025 = 1.11), cemiplimab (ROR025 = 375.35, IC025 = 0.83), ipilimumab (ROR025 = 72.67, IC025 = 3.77), durvalumab (ROR025 = 18.27, IC025 = 0.72), nivolumab (ROR025 = 29.03, IC025 = 3.46) and pembrolizumab (ROR025 = 38.15, IC025 = 3.21). It has not been mentioned in previous studies. Autoimmune nephritis disease is a disease caused by an impaired autoimmune system. The aforementioned medicinal mechanism of the ICIs is very relevant to autoimmune nephritis. Therefore, medical staff must pay attention to the physical condition of such patients in clinical use.

Conclusion

This study comprehensively evaluated the association of ICIs and potential nephrotoxicities from real-world practice. Overall, no significant association was detected between ICIs and kidney AEs, while there was a significant difference between AEs related to nephrotoxicity and atezolizumab in total. And class-specific nephrotoxicities were detected in several ICI immunotherapy strategies. Partial results were consistent with previous literature. The results show that acute kidney injury, IgA nephropathy, and nephritis show a significant difference with partial ICIs. At the same time, discoveries have also emerged. Autoimmune nephritis and a variety of drugs are related, including atezolizumab, cemiplimab, ipilimumab, nivolumab, and pembrolizumab. In the clinical application of ICIs, attention should be paid to patients, especially male patients and elderly patients, with acute kidney injury, nephritis, autoimmune nephritis, and other nephrotoxic AEs. Related AEs of nephrotoxicity are warranted to be reminded by clinicians.

Acknowledgments This study was funded by the National Natural Science Foundation of China (81303315) and the Natural Science Foundation of Liaoning Province (20180550342).

Conflict of Interest The authors declare no conflict of interest

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