Kidney Week 2025 Annual Meeting-Sepsis-Associated AKI: Pathophysiology to Subphenotypes to Treatments

Video Transcription

Video Summary

This conference session focused on sepsis-associated acute kidney injury (SA-AKI), emphasizing its heterogeneous biology and the need for precision approaches to therapy and trials.<br /><br />Dr. Stansky reviewed a new consensus definition: AKI plus consensus sepsis criteria occurring within 7 days of sepsis diagnosis. She emphasized that SA-AKI is often not due to global renal hypoperfusion or classic acute tubular necrosis; global renal blood flow is frequently preserved or increased. Instead, key drivers include (1) dysregulated inflammation (PAMP/DAMP recognition, cytokines, ROS, mitochondrial injury), (2) microcirculatory dysfunction (maldistributed intrarenal perfusion, endothelial activation, thrombosis, shunting, medullary hypoxia), and (3) metabolic reprogramming (cell-cycle arrest, shift to glycolysis, later need for mitochondrial recovery). She highlighted examples of targeted therapies: post-hoc ADRENAL data suggesting hydrocortisone may reduce need for kidney replacement therapy (KRT) in selected patients; iloprost (iMICRO) showing no organ benefit; and the ongoing LIMIT-AKI metformin trial aimed at metabolic pathways.<br /><br />Dr. Kiernan discussed SA-AKI subphenotyping methods: creatinine trajectories (persistence predicts outcomes more than magnitude), genetics (GWAS signals limited by heterogeneity and gene–environment interactions), and biomarker-driven clustering. She presented biomarker phenotypes (e.g., ANG2/ANG1 and sTNFR1) that identified differential treatment response in CLOVERS—restrictive fluids/early vasopressors benefiting a “leaky endothelium” subgroup. She also described endotoxin-enriched trial designs (EUPHRATES/TIGRIS).<br /><br />Dr. Becker summarized trials of recombinant alkaline phosphatase, a detoxifying enzyme that dephosphorylates endotoxin and other pro-inflammatory molecules. Across studies, renal benefits (e.g., MAKE90, reduced KRT) were consistent, but a phase 3 sepsis trial was stopped for futility on mortality despite kidney benefit; post-hoc analyses suggested greater benefit in patients with lower baseline GFR or higher severity. A cardiac surgery trial is underway.<br /><br />Dr. Legrand reviewed the broader AKI therapeutic pipeline, including inflammation/metabolism targets, angiotensin II hemodynamic trials, potential galectin-3 inhibition, SGLT2 inhibitors (mixed acute ICU data but possible chronic protection), and promising endotoxin hemoperfusion results from TIGRIS (per sponsor press release) showing mortality benefit in patients with moderate endotoxemia. Overall, speakers stressed trial enrichment, validated subphenotypes, and multi-pathway targeting.

Asset Subtitle

Moderator(s): Linda Awdishu, Bryan Kestenbaum

Presentation(s):

Pathophysiology in Sepsis-Associated AKI - Natalja Stanski
Identification of Subphenotypes in Sepsis-Associated AKI - Elizabeth Kiernan
Recombinant Alkaline Phosphatase for Sepsis-Associated AKI - Peter Pickkers
What Is on the Horizon in AKI Therapeutics? - Matthieu Legrand

Meta Tag

Date 11/6/2025

Pathway 1 AKI and Critical Care

Pathway 2 Kidney Biology and Physiology

Session ID 507288

Keywords

sepsis-associated acute kidney injury

SA-AKI consensus definition

precision medicine in AKI

microcirculatory dysfunction

endothelial activation and thrombosis

metabolic reprogramming in sepsis

biomarker-driven subphenotypes

creatinine trajectory persistence

CLOVERS trial fluid strategy

endotoxin hemoperfusion TIGRIS

recombinant alkaline phosphatase

kidney replacement therapy outcomes