Kidney Week 2025 Annual Meeting-Emerging Mechanisms of AKI in Cardiovascular-Kidney-Metabolic Syndrome

Video Transcription

Video Summary

This session on “Emerging Mechanisms of AKI and Cardiovascular Kidney Metabolic (CKM) Syndrome” highlighted converging genetic, mitochondrial, lipid, and aging pathways linking acute kidney injury (AKI) with cardiometabolic disease.<br /><br />Dr. Shen Li presented large-scale kidney function GWAS (over 2 million individuals) integrated with kidney eQTL and single-cell epigenomic/transcriptomic data to prioritize causal genes. Her group focused on ferroptosis (iron-dependent lipid peroxidation–driven cell death) as a shared mechanism across kidney and metabolic diseases. They identified LECTB as a CKM risk gene expressed in proximal tubules; lower LECTB associated with worse eGFR, lower HDL, and higher triglycerides. LECTB-deficient mice showed impaired glucose tolerance, higher triglycerides (females), and more severe cisplatin AKI, while proximal-tubule LECTB overexpression was protective. Mechanistically, LECTB’s enzymatic activity cleaves/activates PLA2G6, promoting detoxification of oxidized phosphatidylethanolamines (PE) into lyso-PE, reducing ferroptosis sensitivity; ferroptosis inhibitors improved outcomes in models.<br /><br />Professor Peter Stenvinkel discussed early vascular aging in CKD, emphasizing cellular senescence (p16/p21 upregulation) and suppressed NRF2 antioxidant signaling as therapeutic hubs. He proposed AKI may accelerate systemic/vascular aging via persistent inflammation, epigenetic changes, and senescence, but noted a lack of longitudinal human studies directly linking AKI to vascular dysfunction. Potential interventions include NRF2 activators (with caution from bardoxolone experience), senolytics, and mitochondrial-protective strategies, plus consideration of environmental factors like air pollution that downregulate NRF2 and promote renal senescence.<br /><br />Dr. Amandeep Bajwa focused on obesity-driven mitochondrial dysfunction priming kidneys for AKI. Systemic mitochondrial transplantation improved metabolic parameters, reduced hepatic and renal lipid deposition, and mitigated cisplatin AKI. She also described SS31’s mitochondrial target PLSCR3 and a new oral activator (AB3) protective in AKI models. Finally, she introduced a rapid urine fluorescence assay (resazurin/resorufin) as an early, sensitive marker of tubular mitochondrial health after ischemic injury.<br /><br />Dr. Leslie Gewin highlighted fatty acid oxidation flexibility: despite tubular CPT1A deletion, kidneys maintained function, with compensatory upregulation of peroxisomal fatty acid oxidation genes. She discussed evidence that shifting fatty acid oxidation burden from mitochondria to peroxisomes (including via dietary dicarboxylic acids) may reduce oxidative stress and protect in AKI.

Asset Subtitle

Moderator(s): Sanjeev Kumar, Mark Okusa

Presentation(s):

Novel Genetic Links Between Mitochondrial Dynamics and Lipid Metabolism in CKM Syndrome - Shen Li
AKI as a Promoter of Senescence and Premature Vascular Aging - Peter Stenvinkel
Linking Mitochondrial Dysregulation, Obesity, and AKI in the Landscape of CKM Syndrome - Amandeep Bajwa
Unraveling the Mechanisms of Fatty Acid Oxidation in CKM Syndrome: Central Role of Peroxisomes - Leslie Gewin

ASN thanks the ASN AKINow Basic Science Workgroup for assistance with this session.

Meta Tag

Date 11/8/2025

Pathway 1 AKI and Critical Care

Pathway 2 Pathology

Session ID 505557

Keywords

acute kidney injury (AKI)

cardiovascular kidney metabolic (CKM) syndrome

genome-wide association study (GWAS)

kidney eQTL and single-cell omics

ferroptosis

LECTB

PLA2G6

oxidized phosphatidylethanolamines (PE) detoxification

cellular senescence and early vascular aging

NRF2 antioxidant signaling

mitochondrial dysfunction and mitochondrial transplantation

SS31–PLSCR3 and AB3 mitochondrial activator

peroxisomal fatty acid oxidation and dicarboxylic acids