Weekly Sepsis Research Analysis
This week’s sepsis literature emphasized mechanistic targets linking immunometabolism and immunothrombosis, translational biomarkers for sepsis-associated AKI with therapeutic rescue in animals, and actionable clinical trials/diagnostics that can change bedside care. Key preclinical work identified platelet IRAP-driven ribophagy as a druggable node in septic thrombosis and validated PLTP as a prognostic and therapeutic mediator in SA-AKI. A pragmatic ED pilot RCT of early concentrated albumin de
Summary
This week’s sepsis literature emphasized mechanistic targets linking immunometabolism and immunothrombosis, translational biomarkers for sepsis-associated AKI with therapeutic rescue in animals, and actionable clinical trials/diagnostics that can change bedside care. Key preclinical work identified platelet IRAP-driven ribophagy as a druggable node in septic thrombosis and validated PLTP as a prognostic and therapeutic mediator in SA-AKI. A pragmatic ED pilot RCT of early concentrated albumin demonstrated feasible fluid- and vasopressor-sparing effects, informing larger trials.
Selected Articles
1. IRAP Drives Ribosomal Degradation to Refuel Energy for Platelet Activation during Septic Thrombosis.
Multilevel mechanistic work shows IRAP promotes lysosomal ribosome degradation (ribophagy) in activated platelets during septic thrombosis, supplying amino acids to aerobic glycolysis to sustain prolonged platelet activation. Pharmacologic or genetic blockade of IRAP attenuated platelet hyperactivation and reduced septic thrombosis in preclinical models.
Impact: Uncovers a novel platelet energy-regeneration pathway and nominates IRAP as a druggable node connecting metabolism to immunothrombosis—high conceptual novelty with direct relevance to thrombotic complications in sepsis.
Clinical Implications: If translated, selective IRAP inhibitors could reduce septic immunothrombosis and thromboinflammatory organ injury without broad antiplatelet immunosuppression; translational safety and human validation are required.
Key Findings
- IRAP promotes mTORC1- and S-acylation–dependent lysosomal degradation of ribosomes in activated platelets (ribophagy).
- Amino acids from ribophagy fuel aerobic glycolysis, reprogramming platelet metabolism to sustain activation.
- Targeted IRAP blockade markedly reduced platelet hyperactivation and septic thrombosis in vivo.
2. The role of phospholipid transfer protein in sepsis-associated acute kidney injury.
A prospective ICU cohort measured plasma PLTP activity and showed early PLTP predicts SA-AKI and MAKE30 (AUC ~0.87). Translational CLP mouse experiments demonstrated worse renal outcomes with PLTP deficiency and improved survival/renal function with recombinant PLTP, linking a human biomarker to therapeutic potential.
Impact: Bridges human prognostic biomarker discovery with mechanistic animal rescue experiments, positioning PLTP as both a diagnostic and a candidate therapeutic axis in SA-AKI.
Clinical Implications: Early PLTP measurement could aid SA-AKI risk stratification; recombinant PLTP or PLTP-enhancing interventions merit dose/safety studies and eventual clinical trials for AKI prevention or mitigation.
Key Findings
- Plasma PLTP activity within 24 h independently predicted SA-AKI and MAKE30 with AUC ≈0.87.
- PLTP+/− mice had worse renal outcomes after CLP; recombinant human PLTP improved 10-day survival and renal mitochondrial integrity in CLP mice.
- Prospective human sampling paired with translational animal validation strengthens causality inference.
3. Intervention With Concentrated Albumin for Undifferentiated Sepsis in the Emergency Department (ICARUS-ED): A Pilot Randomized Controlled Trial.
A 464-patient pilot RCT randomized ED patients with suspected infection and hypoperfusion to early 20% albumin (400 mL over 4 hours) versus standard care. The trial was feasible with >95% protocol adherence; albumin did not change 24-hour SBP but reduced total fluid at 72 h, decreased vasopressor requirements at 24/72 h, and improved organ dysfunction without mortality difference.
Impact: A pragmatic randomized pilot that directly informs early resuscitation practice—demonstrates feasible albumin use with fluid- and catecholamine-sparing signals that justify a definitive multicenter RCT with patient-centered outcomes.
Clinical Implications: Early concentrated albumin could be considered in selected ED sepsis patients to reduce fluid and vasopressor exposure; larger, stratified RCTs are needed to evaluate mortality and functional outcomes.
Key Findings
- Protocol adherence >95% and infection confirmed in 95% of 464 enrolled patients.
- No difference in 24-hour SBP between groups; higher SBP at 6 hours in albumin arm.
- Albumin arm had lower total infused fluid at 72 h, fewer patients on vasopressors at 24/72 h, and improved organ dysfunction; mortality unchanged.