Abstract: TH-PO532
Dissecting Deregulated Multicellular Programs in IgA Nephropathy
Session Information
- Glomerular Diseases: Omics, Biomarkers, and Tools
October 24, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Boys, Charlotte May, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany
- McCown, Phillip J., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Saez-Rodriguez, Julio, European Bioinformatics Institute, Cambridge, United Kingdom
Group or Team Name
- NEPTUNE Consortium.
Background
Our understanding of IgA nephropathy pathogenesis is rich, but incomplete. Emerging single-cell data offers the opportunity for improving our understanding of the disease. The Omnibus of CElls And Nuclei (OCEAN) comprises single nucleus data from 11 living donors from the Michigan Human Kidney Transplant Transcriptomic Atlas study and 120 FSGS, MCD, IgAN, and other kidney disease patients from the NEPTUNE consortium. We present the results from an unsupervised exploratory analysis of this dataset with the aim of studying transcriptomic alterations in primary proteinuric glomerular diseases, with a focus on IgA nephropathy.
Methods
Pseudobulk profiles were generated from OCEAN 10x single nucleus data for each cell type and sample. Candidate ligand-receptor interactions were computed using LIANA+. Exploratory data analysis was performed on the resulting pseudobulk profiles and ligand-receptor features using the multicellular factor analysis framework, resulting in unsupervised "factors" which describe the transcriptomic heterogeneity across all samples including living donors. Factors were associated post-hoc with clinical metadata and cell type compositional information by ANOVA. Further analysis focused on factors best explaining patient heterogeneity in (but necessarily not exclusive to) IgAN.
Results
Our computational analysis disentangles transcriptomic alterations in the tubular compartment associated with GFR loss (p val < 1e-10) and patients age (p val < 1e-8) from other more specific pathological changes. We identify further patterns of transcriptomic dysregulation and cell-cell communication which account for heterogeneity among IgAN patient samples, including a factor associated with parietal epithelial cell expansion and loss of podocytes, accompanied by downregulation of SLIT-ROBO signalling, which was also observed in FSGS.
Conclusion
Analysis of NEPTUNE OCEAN single nucleus data not only provides a description of patient heterogeneity in IgAN and reveals pathogenic alterations in the IgAN transcriptome but, crucially, places these in the wider context of nephrotic syndrome and glomerular disease.
Funding
- NIDDK Support