Abstract: SA-PO0125
Whole-Transcriptome Spatial Atlas of Human Alport Syndrome Reveals Cross-Tubular Inflammatory Reprogramming and Loss of Epithelial Identity
Session Information
- ADPKD and Cystic Kidney Disease - 3
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic (Monogenic)
Authors
- Isnard, Pierre, Institut Necker Enfants Malades, Paris, Île-de-France, France
- Knebelmann, Bertrand, Institut Necker Enfants Malades, Paris, Île-de-France, France
- Finkel, Nancy, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts, United States
- Shin, Taehwan, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, Massachusetts, United States
- Pontoglio, Marco, Institut Necker Enfants Malades, Paris, Île-de-France, France
- Terzi, Fabiola, Institut Necker Enfants Malades, Paris, Île-de-France, France
Background
Alport syndrome (AS) is a hereditary glomerulonephritis caused by COL4A3/4/5 mutations, leading to progressive glomerular basement membrane disruption, tubulointerstitial fibrosis, and immune infiltration. The spatial organization and transcriptional complexity of disease-driving populations remain unresolved. Whole-transcriptome spatial profiling now enables high-resolution mapping of AS in situ.
Methods
Six AFA-fixed kidney biopsies (two controls, four AS) were profiled by CosMx Whole Transcriptome (~18,000 genes) spatial transcriptomics with mIF (PanCK, CD45, CD68, CD298/B2M, DAPI). After QC, 224,389 cells were retained. Louvain clustering with targeted sub-clustering identified populations annotated by KPMP/HuBMAP modules, mIF, and LLM-assisted reasoning. DE used pseudobulk DESeq2 and Wilcoxon, with GSEA.
Results
We resolved 25 distinct cell populations. Four were strongly AS-enriched (>80%): CD-intercalated cells (88.4%) suggesting acid-base remodeling; plasmocytes (84.5%) consistent with lymphoplasmocytic infiltrate; injured proximal tubule (83.6%; SPP1+); and macrophages (80.2%). Pseudobulk DE in pooled proximal tubule (n=93,000) revealed 167 dysregulated genes, with GSEA showing coordinated upregulation of inflammatory programs (Allograft rejection NES=+1.8, Inflammatory response NES=+1.7, EMT NES=+1.5) and downregulation of metabolic pathways (OXPHOS NES=-2.1, mTORC1 NES=-1.7). Cell-level analysis revealed additional dysregulated populations: collecting duct principal cells (296 DE; IFN-gamma response NES=+2.2; loss of ID1/ID3/WNT9B developmental programs), thick ascending limb (195 DE; loss of UMOD/SLC12A1), and fibroblasts (85 DE; stromal activation IGFBP5+/MGP+). HLA-DRB1 was consistently upregulated across PT, TAL, and collecting duct, indicating broad MHC-class II induction. Mature populations (PT_S3, TAL_thick_healthy, distal tubule) were Control-enriched (>85%), reflecting loss of differentiated identity. Podocytes showed reduced abundance with downregulated cytoskeletal markers (KRT18, CLDN11) in AS.
Conclusion
This first whole-transcriptome spatial atlas of human AS biopsies reveals coordinated inflammatory activation, MHC-class II induction across tubular segments, and loss of metabolic and developmental programs, providing a high-resolution framework for mechanistic studies of hereditary nephropathies.
Acknowledgment
None
Funding
- Commercial Support – Novartis