Abstract
BackgroundImmune checkpoint inhibitors (ICIs) have brought a paradigm shift to cancer treatment. However, little is known about the risk of renal adverse events (RAEs) of ICI-based regimens, especially ICI combination therapy.MethodsWe carried out a network meta-analysis of randomized controlled trials (RCTs) to compare the risk of RAEs between ICI-based regimens and traditional cancer therapy, including chemotherapy and targeted therapy. Subgroup analysis was conducted based on tumor types.ResultsNinety-five eligible RCTs involving 40,552 participants were included. The overall incidence of RAEs, grade 3–5 RAEs, acute kidney injury (AKI), and grade 3–5 AKI was 4.3%, 1.2%, 1.3%, and 0.8%, respectively. Both ICI-based treatment regimens and traditional cancer therapy showed significantly higher risk of RAEs and AKI than the placebo. Among ICI monotherapy, anti-PD-1 (RR: 0.51, 95%CI: 0.29–0.91) was significantly safer than anti-CTLA-4 in terms of RAEs. Anti-CTLA-4 showed significantly higher toxicity than anti-PD-1 (RR: 0.33, 95%CI: 0.14-0.77), anti-PD-L1 (RR: 0.38, 95%CI:0.16-0.91), and anti-PD-1 plus anti-CTLA-4 (RR: 0.32, 95%CI: 0.12-0.87) in terms of grade 3-5 RAEs. The difference was not significant between ICI monotherapy and traditional cancer therapy, except that targeted therapy seemed the least toxic therapy in terms of the incidence of AKI. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1 (RR: 1.61, 95%CI: 1.02–2.56). The difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICI plus chemotherapy showed increased risk of both RAEs and AKI compared with ICI monotherapy, chemotherapy, and targeted therapy. The overall results remained robust in the meta-regression and sensitivity analyses.ConclusionsAmong ICI monotherapy, anti-CTLA-4 appeared to be associated with increased toxicity, especially in terms of grade 3–5 RAEs. Anti-CTLA-4 plus anti-PD-1 were associated with higher risk of RAEs than anti-PD-1. However, the difference was not significant between other dual ICI regimens and ICI monotherapy in terms of RAEs and AKI. ICIs plus chemotherapy seemed to be the most toxic treatment regimen in terms of RAEs, AKI, and grade 3–5 AKI.Systematic Review RegistrationPROSPERO, identifier CRD42020197039.
Highlights
Immune checkpoint inhibitor (ICI) therapy has unveiled a new era in cancer treatment, yielding an unprecedented and robust response in the treatment of different malignancies
A total of 95 eligible randomized clinical trials (RCTs) involving 40,552 participants were selected in the network meta-analysis
The anti-programmed cell death 1 (PD-1) plus chemotherapy, antiPD-1 plus anti-cytotoxic Tlymphocyte antigen 4 (CTLA-4), and anti-PD-1 plus targeted therapy were associated with relatively higher rate of renal adverse events (RAEs), grade 3–5 RAEs, acute kidney injury (AKI), and grade 3–5 AKI than other regimens
Summary
Immune checkpoint inhibitor (ICI) therapy has unveiled a new era in cancer treatment, yielding an unprecedented and robust response in the treatment of different malignancies. These ICIs release inactive immune responses by blocking specific downregulators of the immune response including cytotoxic Tlymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) and its ligand, programmed cell death ligand 1 (PD-L1) [1]. It functions by binding to its ligand PD–L1 on the antigenpresenting cells, leading to T cells exhaustion and inhibiting their capacity of activation and differentiation [7, 8] By targeting these immune checkpoints, ICIs can reinvigorate T cell activity and augment antitumor immunity. Little is known about the risk of renal adverse events (RAEs) of ICI-based regimens, especially ICI combination therapy
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