Daily Sepsis Research Analysis
Analyzed 45 papers and selected 3 impactful papers.
Summary
Analyzed 45 papers and selected 3 impactful articles.
Selected Articles
1. Ticagrelor protects sepsis-associated acute kidney injury by modulating renal gluconeogenesis and inflammation through the P2Y12 receptor in proximal tubule cells.
This translational study identifies P2Y12 signaling in renal proximal tubules as a driver of inflammation and impaired gluconeogenesis in SA-AKI. Genetic deletion or ticagrelor-mediated inhibition restored cAMP-PKA signaling, reduced cytokine production, preserved gluconeogenesis, and mitigated kidney injury.
Impact: Reveals a previously unrecognized, druggable mechanism in SA-AKI and supports repurposing a widely available antiplatelet agent. Provides strong mechanistic convergence using imaging, genetics, and pharmacology.
Clinical Implications: Suggests that P2Y12 antagonism (e.g., ticagrelor) could be evaluated as a renoprotective strategy in SA-AKI, with careful assessment of bleeding risk and dosing. Biomarkers of tubular P2Y12 activity may help select candidates for future trials.
Key Findings
- P2Y12 expression is upregulated in proximal tubule cells after LPS exposure.
- P2Y12 activation triggers Gi signaling, suppresses cAMP-PKA, increases cytokines, and disrupts gluconeogenesis.
- Single-molecule imaging visualizes P2Y12–Gi interactions in tubular cells.
- Genetic deletion or ticagrelor inhibition of P2Y12 restores signaling, reduces inflammation, preserves gluconeogenesis, and mitigates SA-AKI in vivo.
Methodological Strengths
- Convergent validation across genetics, pharmacology, and single-molecule imaging
- In vivo and in vitro models with mechanistic linkage to function (gluconeogenesis, signaling)
Limitations
- Preclinical models; human validation is lacking
- Systemic P2Y12 inhibition may carry bleeding risk and off-target effects beyond the kidney
Future Directions: Early-phase clinical trials of ticagrelor in SA-AKI with mechanistic biomarkers (e.g., urinary cAMP-PKA readouts) and stratification by inflammatory burden; exploration of renal-targeted P2Y12 modulation.
Sepsis-associated acute kidney injury (SA-AKI) is characterized by tubular inflammation and impaired metabolism, yet effective treatments remain lacking. Here, we identify the purinergic receptor P2Y12 as a key regulator of these pathological processes in renal proximal tubule cells. P2Y12 expression is markedly upregulated after lipopolysaccharide challenge. Mechanistically, P2Y12 activation promotes Gi signaling, suppresses the cAMP-PKA pathway, increases proinflammatory cytokine production, and disrupts gluconeogenesis. Using single-molecule imaging, we directly visualize the interaction between P2Y12 and Gi proteins in tubular cells. Genetic deletion of P2Y12 or pharmacological inhibition with ticagrelor, a clinically approved P2Y12 antagonist, restores cAMP-PKA signaling, attenuates inflammation, and preserves gluconeogenic function, ultimately mitigating kidney injury. These findings uncover a previously unrecognized role of P2Y12 in SA-AKI and highlight the therapeutic potential of targeting P2Y12 signaling with existing drugs. Our study provides new mechanistic insight and suggests a promising strategy for repurposing ticagrelor in the treatment of SA-AKI.
2. Emulating a target trial of early compared with late initiation of appropriate antibiotic therapy for hospital-acquired monobacterial Gram-negative bloodstream infections.
In a multi-centre target-trial emulation of 680 monobacterial Gram-negative HA-BSIs, early appropriate therapy reduced 14-day mortality (aHR 0.41) and 28-day mortality (aHR 0.66). Benefits persisted in carbapenem-resistant infections, with consistent results across sensitivity analyses.
Impact: Provides robust quasi-experimental evidence supporting prompt appropriate antibiotics in HA-GNB bloodstream infections, including resistant organisms. Applies modern causal inference (IPW, time-dependent treatment) across 22 hospitals.
Clinical Implications: Reinforces systems for rapid organism identification, early effective coverage, and timely de-escalation. Stewardship programs should prioritize reducing time-to-appropriate therapy, especially for carbapenem-resistant GNB.
Key Findings
- Early appropriate therapy lowered 14-day mortality (14.7% vs 42.9%; aHR 0.41, 95% CI 0.28–0.61).
- 28-day mortality was also reduced with early therapy (aHR 0.66, 95% CI 0.50–0.86).
- Effects persisted in carbapenem-resistant Gram-negative infections (14-day aHR 0.36; 28-day aHR 0.60).
- Consistent findings across prespecified and post hoc analyses using inverse probability weighting and time-dependent models.
Methodological Strengths
- Target-trial emulation with inverse probability weighting and time-dependent exposure modeling
- Multi-centre prospective cohort across 22 hospitals with robust sensitivity analyses
Limitations
- Observational design with potential residual confounding despite advanced methods
- Generalizability may vary by local resistance patterns and diagnostic turnaround times
Future Directions: Implementation studies to reduce time-to-appropriate therapy and evaluate impacts on resistance and length of stay; RCTs where feasible, and integration with rapid diagnostics and stewardship pathways.
BACKGROUND: Delays in appropriate antimicrobial therapy can increase the risk of all-cause mortality (ACM) in hospital-acquired bloodstream infections (HA-BSIs) caused by Gram-negative bacteria (GNB). We aimed to evaluate the effectiveness of early appropriate antimicrobial therapy (EAAT) compared with late appropriate antimicrobial therapy (LAAT) in this population. METHODS: This study used data from a multi-centre, prospective cohort including adult patients with HA-BSI caused by GNB across 22 Turkish hospitals. A hypothetical target trial allocating participants with HA-BSI caused by monobacterial GNB to either EAAT or LAAT was emulated using the weighting approach. The primary outcome was 14 day ACM; 28 day ACM was a secondary outcome. Cox proportional hazards models with inverse probability weighting were applied to account for confounding, with antibiotic treatment incorporated as a time-dependent variable. RESULTS: Among 680 patients, 14 day ACM occurred in 14.7% (40/272) of the EAAT group and 42.9% (175/408) of the LAAT group. EAAT was associated with a lower risk of 14 day ACM [adjusted hazard ratio (aHR) = 0.41; 95% CI: 0.28-0.61). Similarly, 26.1% (71/272) of the patients treated with EAAT and 49.5% (202/408) of those receiving LAAT died during 28 day follow-up (aHR = 0.66; 95% CI: 0.50-0.86). In the carbapenem-resistant GNB subset, EAAT reduced the hazard of 14 day ACM (aHR = 0.36; 95% CI: 0.21-0.60) and 28 day ACM (aHR = 0.60; 95% CI: 0.44-0.84). All prespecified and post hoc analyses consistently supported these findings. CONCLUSIONS: EAAT was associated with a survival benefit in individuals with HA-BSI due to GNB. Although these findings support early initiation of appropriate therapy, residual confounding cannot be excluded.
3. Early enteral nutrition and dynamic metabolic-inflammatory trajectories in sepsis: a retrospective cohort study.
Among 3,354 ICU sepsis patients, EEN was associated with favorable albumin trajectories and reduced assignment to elevated lactate and procalcitonin patterns. Joint modeling revealed that EEN decreased the likelihood of entering an inflammatory surge pattern linked to higher 28-day mortality.
Impact: Links a standard supportive therapy (EEN) to integrated biomarker trajectories that may mechanistically explain mortality benefits, using advanced longitudinal modeling on a large cohort.
Clinical Implications: Supports early enteral feeding protocols in sepsis and suggests monitoring albumin–lactate–PCT trajectories to identify patients trending toward high-risk inflammatory surges.
Key Findings
- EEN was associated with more favorable albumin trajectories and lower odds of elevated lactate and PCT patterns.
- A joint trajectory model defined three classes; EEN reduced assignment to intermediate (OR 0.66) and high-risk inflammatory surge (OR 0.57) classes.
- The high-risk inflammatory surge class had significantly higher 28-day mortality.
Methodological Strengths
- Large ICU cohort with longitudinal biomarker data and group-based trajectory modeling
- Multivariate joint trajectory analysis linking patterns to 28-day mortality
Limitations
- Single-center retrospective design with potential residual confounding
- Definitions and timing of EEN initiation may vary; unmeasured nutritional and hemodynamic factors could influence trajectories
Future Directions: Prospective trials testing EEN timing/intensity stratified by biomarker trajectory class; external validation of trajectory-based risk tools and integration with nutrition protocols.
BACKGROUND: Early enteral nutrition (EEN) is an important part of sepsis management, but its physiological effects are not fully understood. This study examined whether EEN influences the time course of metabolic and inflammatory biomarkers in patients with sepsis. METHODS: We performed a retrospective cohort study of 3,354 adult ICU patients with sepsis admitted to West China Hospital from 2011 to 2025. Group-based trajectory modeling was used to characterize longitudinal patterns of albumin, lactate, and procalcitonin. Associations between EEN and trajectory membership were assessed using multinomial logistic regression. The relationship between trajectory groups and 28-day mortality was further evaluated. RESULTS: Distinct trajectory groups were identified for each biomarker, reflecting heterogeneous nutritional, metabolic, and inflammatory responses. EEN was associated with more favorable albumin trajectories and lower odds of belonging to elevated lactate and procalcitonin patterns. In the multivariate joint trajectory model integrating all three biomarkers, three classes emerged: a stable-low inflammation pattern (67.5%), an intermediate-transient pattern (21.7%), and a high-risk inflammatory surge pattern (10.8%). EEN was independently associated with reduced likelihood of assignment to the intermediate (OR 0.66; 95% CI, 0.52-0.84) and high-risk (OR 0.57; 95% CI, 0.38-0.88) classes. The high-risk trajectory group showed significantly increased 28-day mortality. CONCLUSION: Initiation of EEN was linked to a higher probability of remaining in low-risk albumin-lactate-PCT trajectories and a lower probability of entering the high-risk inflammatory surge pattern. This pattern-level shift may partly explain the observed reduction in short-term mortality associated with EEN.