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Kidney Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: A Systematic Review and Bayesian Network
Shehjar R Trisal1, Gary Low1,2, Faraz Pathan1,2
1Department of Medicine, University of Sydney Nepean Clinical School, Kingswood, New South Wales, Australia.
Background:
The blockade of immune regulatory sites, cytotoxic T-lymphocyte antigen 4, programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) with immune checkpoint inhibitors has revolutionized survival outcomes in patients with cancer. However, immune checkpoint inhibitors are associated with a range of immune-related adverse events. The aim of this network meta-analysis was to evaluate severe adverse kidney events in patients with oncological or hematological malignancy receiving monotherapy, dual therapy, or combined therapy treatment with immune checkpoint inhibitors when compared with either placebo or standard chemotherapy.
Methods:
Phase 3 randomized control trials reporting severe grade (3-5) adverse kidney events were identified across five electronic databases from inception to May 2022. This was supplemented with hand searching of medical journals and the National Clinical Trials registry. A Bayesian network meta-analysis was performed for AKI, hypertension, CKD, and the composite of all acute kidney adverse events. The results are reported as per the PRISMA guidelines.
Results:
Ninety-five randomized control trials reported severe grade adverse kidney events. The risk of developing severe AKI is higher among patients who received PD-1 plus chemotherapy (odds ratio [OR], 1.8; 95% credible interval [CrI], 1.4 to 2.5) and PD-L1 plus chemotherapy (OR, 1.8; 95% CrI, 1.2 to 2.7) compared with standard chemotherapy and placebo (94 studies, 63,357 participants). The risk of developing the composite of all severe acute kidney adverse events is higher among patients who received PD-1 plus chemotherapy (OR, 1.6; 95% CrI, 1.1 to 2.3) and PD-L1 plus chemotherapy (OR, 1.7; 95% CrI, 1.1 to 2.8) when compared with standard chemotherapy and placebo (95 studies, 63,973 participants).
Conclusions:
The combined regimen of PD-1 plus chemotherapy and PD-L1 plus chemotherapy was associated with higher incidence of severe AKI and the composite of all severe acute kidney adverse events.
Podcast:
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_07_10_CJN0000000000000160.mp3.
Insights
Immune checkpoint inhibitors combined with chemotherapy increase the risk of severe acute kidney injury (AKI) and other kidney adverse events in cancer patients. This finding highlights potential kidney toxicity concerns with combination immunotherapies.
Area of Science:
- Nephrology
- Oncology
- Immunology
Background:
- Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte antigen 4, programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) have improved cancer survival.
- However, ICIs are linked to immune-related adverse events, including kidney complications.
Purpose of the Study:
- To evaluate severe adverse kidney events in cancer patients receiving ICI monotherapy, dual, or combined therapy.
- To compare these events against placebo or standard chemotherapy using a network meta-analysis.
Main Methods:
- A Bayesian network meta-analysis of 95 Phase 3 randomized control trials (RCTs) was conducted.
- Data on severe grade (3-5) acute kidney injury (AKI), hypertension, chronic kidney disease (CKD), and composite acute kidney events were analyzed.
- Searches covered electronic databases up to May 2022, supplemented by trial registries and hand searching.
Main Results:
- Combination therapy with PD-1 plus chemotherapy or PD-L1 plus chemotherapy significantly increased the risk of severe AKI compared to standard chemotherapy and placebo.
- Similarly, these combination regimens elevated the risk of a composite of all severe acute kidney adverse events.
- Specific odds ratios (ORs) for severe AKI were 1.8 (95% CrI, 1.4-2.5) for PD-1 plus chemo and 1.8 (95% CrI, 1.2-2.7) for PD-L1 plus chemo.
Conclusions:
- Combined PD-1/PD-L1 plus chemotherapy regimens are associated with a higher incidence of severe AKI and composite acute kidney adverse events.
- These findings underscore the importance of monitoring kidney function in cancer patients undergoing combination immunotherapy.
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