Inflammatory cell-death-associated plasma signatures and lactate-associated metabolic stress in sepsis-associated acute kidney injury: a retrospective biomarker cohort study
Year: 2026
Type: article
Abstract: Background Sepsis-associated acute kidney injury (SA-AKI) is an inflammatory organ-injury syndrome in which regulated cell-death-associated molecular signals and metabolic stress may coexist. Pyroptosis-, ferroptosis-, necroptosis-, and damage-associated molecular pattern (DAMP)-related markers have been implicated in septic tubular injury, while circulating lactate reflects systemic metabolic stress and may participate in immune-metabolic signaling. We investigated whether concurrent circulating cell-death-associated signatures, interpreted together with lactate-associated metabolic stress, could be used to characterize SA-AKI severity and adverse outcomes. Methods This single-center retrospective cohort included 274 adult patients with sepsis admitted to the intensive care unit. The plasma biomarkers for admission comprised GSDMD-NT, active caspase-1, IL-18, IL-1β, and NLRP3 (for pyroptosis); GPX4, MDA, ACSL4, and 4-HNE (for ferroptosis); RIPK3 and p-MLKL (for necroptosis); and HMGB1 and S100A8/A9 (for DAMPs). The lactate level at admission was analyzed as a metabolic stress marker and integrated into the correlation, exploratory univariable outcome, and discrimination analyses. SA-AKI was defined by the KDIGO criteria; the primary outcome was 28-d all-cause mortality, while renal non-recovery at 90 d was one of the secondary outcomes. Results SA-AKI occurred in 186/274 patients (67.9%). The median lactate level at admission was higher in SA-AKI than sepsis without acute kidney injury (AKI) (3.6 [2.4–5.2] vs. 2.1 [1.4–3.0] mmol/L; p < 0.001). The GSDMD-NT, IL-18, MDA, ACSL4, RIPK3, HMGB1, and S100A8/A9 levels increased progressively with AKI severity, whereas GPX4 level decreased (all p < 0.001). The lactate level was positively correlated with GSDMD-NT (ρ = 0.48), MDA (ρ = 0.44), HMGB1 (ρ = 0.44), and RIPK3 (ρ = 0.38) levels and inversely with GPX4 (ρ = −0.40; all adjusted p < 0.001). The exploratory univariable analysis showed the associations of clinical severity, lactate level, and several cell-death-associated biomarkers with 28-d mortality. The combined cell-death/clinical panel yielded an apparent area under the curve of 0.851 (95% confidence interval: 0.800–0.902) in the same cohort and should be regarded as exploratory rather than internally or externally validated performance. Conclusion SA-AKI is characterized by a circulating inflammatory cell-death-associated and metabolic-stress phenotype. The covariation of pyroptosis-, ferroptosis-, necroptosis-, and DAMP-associated plasma markers with lactate level, kidney injury, and study outcomes supports an association-based “metabolic-stress–cell-death–inflammation” framework. These findings are hypothesis-generating and require external validation and mechanistic confirmation; the present data do not establish the causal effects of lactate or tissue-level execution of specific renal cell-death pathways.
Authors: Yang Yu, Yan Xiao, Shuming Pan
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225656322