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

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.

Fig. 1. All signals showing reporting odds ratios (RORs) of immune checkpoint inhibitor (ICI) drugs in detailed nephrotoxic adverse events (AEs). PT, preferred term; ROR025, the lower end of the 95% confidence interval of ROR. ROR025 greater than 1 was deemed a signal.

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in aiding signal detection in spontaneous reporting systems. In a previous study, the ROR was selected as the impropernationality 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 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 nephtoxicities based on more than 50 million records in the appropriate period. This makes our conclusion more stable compared with those of other studies.

Fig. 2. All signals showing information components (ICs) of immune checkpoint inhibitor (ICI) drugs in detailed nephrotoxic adverse events (AEs). PT, preferred term; IC025, the lower end of the 95% confidence interval of IC. IC025 greater than 0 was deemed a signal.

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 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 kidneys are 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 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 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).

References

Chen, G., Qin, Y., Fan, Q., Zhao, B., Mei, D. & Li, X. (2020) Renal adverse effects following the use of different immune checkpoint inhibitor regimens: a real-world pharmacoepidemiology study of post-marketing surveillance data. Cancer Med., 9, 6576-6585. Cortazar, F.B., Marrone, K.A., Troxell, M.L., Ralto, K.M., Hoenig, M.P., Brahmer, J.R., Le, D.T., Lipson, E.J., Glezerman, I.G., Wolchok, J., Cornell, L.D., Feldman, P., Stokes, M.B., Zapata, S.A., Hodi, F.S., et al. (2016)

 Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int., 90, 638-647. Curran, M.A., Montalvo, W., Yagita, H. & Allison, J.P. (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. U. S. A., 107, 4275- 4280. Hellmann, M.D., Paz-Ares, L., Bernabe Caro, R., Zurawski, B., Kim, S.W., 

Carcereny Costa, E., Park, K., Alexandru, A., Lupinacci, L., de la Mora Jimenez, E., Sakai, H., Albert, I., Vergnenegre, A., Peters, S., Syrigos, K., et al. (2019) Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N. Engl. J. Med., 381, 2020-2031. Hoste, E.A.J., Bagshaw, S.M., Bellomo, R., Cely, C.M., Colman, R., Cruz, D.N., Edipidis, K., Forni, L.G., Gomersall, C.D., Govil, D., Honoré, P.M., Joannes-Boyau, O., Joannidis, M., Korhonen, A.-M., Lavrentieva, A., et al. (2015)

 Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study. Intensive Care Med., 41, 1411-1423. Hu, F., Ye, X., Zhai, Y., Xu, J., Guo, X., Guo, Z., Zhou, X., Ruan, Y., Zhuang, Y. & He, J. (2020) Ear and labyrinth toxicities induced by immune checkpoint inhibitors: a disproportionality analysis from 2014 to 2019. Immunotherapy, 12, 531-540.