Kidney Week 2025 Annual Meeting-CKD: Exploring Intertwined Mechanisms of Disease Progression

Video Transcription

Video Summary

The session “CKD Exploring Intertwined Mechanisms” featured short talks spanning human tissue multi-omics, animal and translational models, and mechanistic drivers of inflammation and fibrosis.<br /><br />Dr. Victor Martinez (UPenn) presented an integrated human kidney-tissue metabolomics/transcriptomics/genetics study (333 samples; ~800 metabolites). Healthy tissue was enriched for NAD/FAD, whereas CKD showed accumulation of NAD catabolites, suggesting metabolic exhaustion. Cross-species comparison in a folic-acid mouse model showed only ~40% overlap and inconsistent directionality, emphasizing human specificity. Pathway analyses highlighted TCA cycle and nicotinamide metabolism disruptions. Integrating kidney eQTL/mQTL with a large eGFR GWAS implicated NAT8 and N‑acetyl isoleucine; Mendelian randomization supported N‑acetyl isoleucine as a putatively causal metabolite linked to lower eGFR, proposing a mechanism where NAT8-driven acetylation diverts isoleucine from energy metabolism, promoting tubular injury.<br /><br />Fanjie Zhang described cell- and stage-specific roles of angiopoietin-2 (ANGPT2). In cohorts, higher kidney ANGPT2 correlated with worse eGFR, more fibrosis, and higher risk of kidney failure/death. In adenine CKD, global ANGPT2 deletion improved function, capillary rarefaction, macrophage infiltration, and fibrosis, with transcriptomic shifts toward peroxisomal fatty-acid oxidation. Endothelial ANGPT2 drove early endothelial activation/inflammation, while tubular ANGPT2 dominated advanced disease.<br /><br />Denise Kimbrough examined pyelonephritis-driven renal scarring despite antibiotics. Mouse and human spatial profiling showed persistent immune infiltrates and TGF‑β pathway activity, with distinct spatial separation between TGF‑β–producing cells and downstream fibrotic transcripts, arguing for combined antimicrobial and anti-fibrotic strategies.<br /><br />Additional talks covered: TED1 as a repressor of fibroblast activation (possibly via RUNX2); cathepsin L promoting tubular injury and fibrosis with a proposed natural compound inhibitor; single-nucleus RNA-seq in a swine CKD model implicating endothelial pro-fibrotic programs and LAMA3; TIP60 deficiency promoting cell-cycle arrest and necroptosis; endogenous adenine/MTAP as a senescence driver in aging kidney; and human-genetic validation of SLC6A19 loss-of-function variants protecting kidney function, supporting pharmacologic inhibition.

Asset Subtitle

Moderator(s): Shreeram Akilesh, Tobias Huber

Presentation(s):

Uncovering the Metabolic Architecture of CKD Through Integrated Metabolomics, Transcriptomics, and Genetics of Human Kidney Tissue - Victor Martinez Leon
Distinct Roles of Endothelial and Tubular Angiopoietin-2 in CKD Progression: Inflammation, Fibrosis, and Metabolic Reprogramming - Fan-Chi Chang
Chronic Inflammation Drives Renal Scarring in Mice and Humans with Pyelonephritis - Denise Kimbrough
TEAD1 Regulates Fibroblast Activation and Renal Fibrosis in CKD - Melanie Tran
Targeted Inhibition of Cathepsin L Attenuates Renal Fibrosis - Huini Chen
Single-Nuclear Transcriptomics Reveal Distinct Profibrotic Genes in Proximal Tubular and Endothelial Cells in a Novel Swine Model of CKD - Alejandro Chade
Tip60 Downregulation Induces Cell Cycle Arrest and Z-mtDNA-Dependent Necroptosis by Impairing Aurora-B Kinase Activity in CKD Progression - Yanfang Xu
Multimodal Spatial Imaging Reveals Endogenous Adenine as a Metabolic Inducer of Senescence in Aging Kidneys - Soumya Maity
Experimentally Validated SLC6A19 Loss-of-Function Variants Improve Kidney Function and Reduce Progression to Kidney Failure - Sahar Mozaffari

Note: Continuing education credits are not being offered for this session.

Meta Tag

Date 11/6/2025

Pathway 1 CKD Non-Dialysis

Session ID 519920

Keywords

chronic kidney disease

kidney multi-omics

metabolomics transcriptomics genetics integration

NAD FAD metabolism

TCA cycle disruption

NAT8

N-acetyl isoleucine

eGFR GWAS Mendelian randomization

angiopoietin-2 ANGPT2

endothelial activation and inflammation

macrophage infiltration and fibrosis

TGF-beta signaling renal scarring

single-nucleus RNA-seq swine CKD model

SLC6A19 loss-of-function kidney protection