Increased circulatory Krebs cycle metabolites in sepsis is associated with increased interleukin-6 release and worse survival

Kuei-Pin Chung; Yi-Hsuan Chen; Yi-Jung Chen; Jung-Yien Chien; Han-Chun Kuo; Yen-Tsung Huang; Sheng-Yuan Ruan; Yu-Li Lin; Yen-Fu Chen; Li-Ta Keng; Lu-Cheng Kuo; Shih-Chi Ku; Ching-Hua Kuo; Chong-Jen Yu; TAiwan CollaboraTive Intensive Care Study group(TACTICS)

doi:10.1097/SHK.0000000000002550

Increased circulatory Krebs cycle metabolites in sepsis is associated with increased interleukin-6 release and worse survival

Shock. 2025 Jan 14. doi: 10.1097/SHK.0000000000002550. Online ahead of print.

Affiliations

¹ Department of Laboratory Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
³ NTU Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, Taiwan.
⁴ Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
⁵ Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan.
⁷ Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.

PMID: 39836931
DOI: 10.1097/SHK.0000000000002550

Abstract

Objective: Recent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study.

Methods: This prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate and malate.

Results: In total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and non-survivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality.

Conclusions: Study findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.