Time-varying metoprolol exposure and the risk of acute kidney injury: a multicenter retrospective cohort study
- 1920th Hospital of the Joint Logistics Support Force of the Chinese People’s Liberation Army
- 2Department of Pharmacy, Guandu District People’s Hospital
Abstract
Background: Evidence regarding the association between metoprolol use and acute kidney injury (AKI) remains limited, particularly because of time-varying exposure, cardiovascular confounding, and uncertain temporal ordering. We evaluated the association between recent metoprolol exposure and incident AKI using a longitudinal time-varying framework.
Methods: This multicenter retrospective longitudinal cohort study included adult inpatients from three Chinese hospitals between January 2020 and December 2024. Eligible patients had an estimated glomerular filtration rate ≥60 mL min ⁻¹ ·1.73 m ⁻² at cohort entry and sufficient serial serum creatinine (Scr) and medication execution records. Metoprolol was modeled as a lag-1 time-varying exposure, relating use on hospital day t to AKI risk on day t +1. Incident AKI was identified using rolling KDIGO Scr criteria. Time-varying Cox regression adjusted for demographic characteristics, baseline renal function, major comorbidities, baseline severity-related factors, and lagged concomitant medication exposures. Sensitivity and complementary analyses evaluated the robustness of the findings.
Results: Among 291,049 screened hospitalizations, 20,333 patients contributed 284,470 risk intervals, and 1,050 developed incident AKI. Lag-1 metoprolol exposure was associated with a higher AKI hazard in the unadjusted model (HR, 2.53; 95% CI, 2.13–3.00). The association was substantially attenuated after adjustment but remained statistically significant in the primary model (HR, 1.37; 95% CI, 1.05–1.79; P = 0.022). Prespecified follow-up-time analyses suggested that the association was concentrated during the first 72 h after cohort entry. Sensitivity analyses generally yielded estimates in the same direction, although the magnitude and statistical significance varied across analytical specifications; the association was attenuated to non-significance in the 2-day lag analysis (HR, 1.27; 95% CI, 0.96–1.68) and after additional adjustment for vasopressor use (HR, 1.29; 95% CI, 0.98–1.70). No consistent monotonic dose–response relationship was observed.
Conclusion: Recent metoprolol exposure was associated with a modestly higher hazard of incident AKI in the primary adjusted analysis. However, attenuation after adjustment, temporal heterogeneity, sensitivity to exposure timing and confounding control, and the absence of a consistent monotonic dose–response pattern suggest that residual confounding and clinical treatment context may contribute to the observed association. These findings should be interpreted as a hypothesis-generating short-term AKI safety signal rather than evidence of direct metoprolol nephrotoxicity or causality.
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BibTeX
@article{li2026timevarying,
title = {{Time-varying metoprolol exposure and the risk of acute kidney injury: a multicenter retrospective cohort study}},
author = {Zhengfu Li and Hongkai Zha and Qingyun Gong and Meixian Wu and Yanyun She and Fan Xu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1899992},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1899992/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Time-varying metoprolol exposure and the risk of acute kidney injury: a multicenter retrospective cohort study
AU - Zhengfu Li
AU - Hongkai Zha
AU - Qingyun Gong
AU - Meixian Wu
AU - Yanyun She
AU - Fan Xu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1899992
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1899992/full
AB - Background: Evidence regarding the association between metoprolol use and acute kidney injury (AKI) remains limited, particularly because of time-varying exposure, cardiovascular confounding, and uncertain temporal ordering. We evaluated the association between recent metoprolol exposure and incident AKI using a longitudinal time-varying framework. Methods: This multicenter retrospective longitudinal cohort study included adult inpatients from three Chinese hospitals between January 2020 and December 2024. Eligible patients had an estimated glomerular filtration rate ≥60 mL min ⁻¹ ·1.73 m ⁻² at cohort entry and sufficient serial serum creatinine (Scr) and medication execution records. Metoprolol was modeled as a lag-1 time-varying exposure, relating use on hospital day t to AKI risk on day t +1. Incident AKI was identified using rolling KDIGO Scr criteria. Time-varying Cox regression adjusted for demographic characteristics, baseline renal function, major comorbidities, baseline severity-related factors, and lagged concomitant medication exposures. Sensitivity and complementary analyses evaluated the robustness of the findings. Results: Among 291,049 screened hospitalizations, 20,333 patients contributed 284,470 risk intervals, and 1,050 developed incident AKI. Lag-1 metoprolol exposure was associated with a higher AKI hazard in the unadjusted model (HR, 2.53; 95% CI, 2.13–3.00). The association was substantially attenuated after adjustment but remained statistically significant in the primary model (HR, 1.37; 95% CI, 1.05–1.79; P = 0.022). Prespecified follow-up-time analyses suggested that the association was concentrated during the first 72 h after cohort entry. Sensitivity analyses generally yielded estimates in the same direction, although the magnitude and statistical significance varied across analytical specifications; the association was attenuated to non-significance in the 2-day lag analysis (HR, 1.27; 95% CI, 0.96–1.68) and after additional adjustment for vasopressor use (HR, 1.29; 95% CI, 0.98–1.70). No consistent monotonic dose–response relationship was observed. Conclusion: Recent metoprolol exposure was associated with a modestly higher hazard of incident AKI in the primary adjusted analysis. However, attenuation after adjustment, temporal heterogeneity, sensitivity to exposure timing and confounding control, and the absence of a consistent monotonic dose–response pattern suggest that residual confounding and clinical treatment context may contribute to the observed association. These findings should be interpreted as a hypothesis-generating short-term AKI safety signal rather than evidence of direct metoprolol nephrotoxicity or causality.
SN - 1663-9812
ER -