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Page 10 of 12 Yu et al. Hepatoma Res. 2025;11:29 | https://dx.doi.org/10.20517/2394-5079.2025.47

Creatinine is a metabolic byproduct produced by skeletal muscle during energy metabolism; it is primarily
filtered from the blood and excreted by the kidneys. Elevated baseline serum creatinine levels, indicating
impaired renal function, may slow the clearance of pro-inflammatory cytokines produced during TACE in
HCC patients. This delayed clearance could potentially prolong and amplify systemic immune activation
and inflammatory status, thereby increasing the risk and severity of irAEs. In this study, creatinine in the
sirAEs group was 58.23 ± 25.86, which was significantly higher than that in the control group (44.18 ±
31.87). This may suggest that patients with poor renal function reserve are more likely to develop sirAEs
after immunotherapy. Previous studies have also shown that high levels of creatinine are more likely to lead
to acute kidney injury after immunotherapy . NLR reflects the balance between tumor inflammatory
[20]
response and antitumor immunity. This study showed that NLR in the sirAEs group was 1.79 ± 1.16, which
was significantly lower than 3.42 ± 1.58 in the control group. NLR was an independent risk factor for
sirAEs, and its AUC was 0.793. Studies have shown that a high level of NLR is closely associated with a
reduction in the incidence of irAEs (≥ 2 grade) after immunotherapy for HCC , which is consistent with
[21]
the conclusion observed in a variety of other malignant tumors [21-26] . Some studies have reported that a high
NLR is associated with increased toxicity, which contrasts with our findings. This discrepancy may stem
from the distinct treatment context of our study, which involved HCC patients receiving combined TACE
and immunotherapy. In this specific setting, a low baseline NLR may reflect an immune system that is not
overly suppressed or exhausted by chronic inflammation. As a result, when primed by the potent antigen
release and inflammatory cascade induced by TACE, such an immune system may mount a more vigorous
and effective lymphocytic proliferation and activation in response to subsequent immune checkpoint
inhibition. This “overly effective” immune activation, while enhancing antitumor response, could also more
readily break self-tolerance, thereby predisposing patients to sirAEs.

Although our prediction model provides valuable prognostic information, it also has some limitations.
First, our study sample came from a single medical center and lacked external validation in a large
population or across regions, which may limit the external validity of the results. Second, because this study
was retrospective and relied on available medical records, some of the test data were not comprehensive
enough. Finally, some patients received immunotherapy and targeted therapy at the same time, so the
occurrence of sirAEs in some patients cannot exclude the factor of targeted therapy. We look forward to
designing and conducting multi-center prospective studies in the future for validation. Despite its
limitations, this model can predict the occurrence of IRE using readily available clinical data, making it
easier to implement in clinical practice.

In conclusion, by collecting data of lymphocyte subsets and clinical characteristics of HCC patients before
immunotherapy, the nomogram prediction model for predicting the occurrence of sirAEs in HCC can
effectively help clinicians to identify HCC patients who are likely to develop sirAEs.

DECLARATIONS

Authors’ contributions
Material preparation, data collection and analysis: Yu Z, Leng B, You R, Diao L
Writing the first draft of the manuscript: Yu Z
Contributing to the conception and design of the study: Yu Z, You R, Wang C, Leng B, Diao F, Xu Q, Yin G

Commenting on the previous versions of the manuscript: Yu Z, You R, Wang C, Leng B, Diao F, Xu Q, Yin G
Yin G is the corresponding author of this study. All authors have read and approved the final version of the
manuscript.