Abstract: TH-PO459
Resolving Focal Segmental Glomerulosclerosis Recurrence in Human Allografts at Single Cell Resolution
Session Information
- Glomerular Diseases: Podocytopathies and Nephrotic Syndromes
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1302 Glomerular Diseases: Immunology and Inflammation
Authors
- McDaniels, Jennifer M., University of Maryland Baltimore, Baltimore, Maryland, United States
- Shetty, Amol C., University of Maryland Baltimore, Baltimore, Maryland, United States
- Rousselle, Thomas, University of Maryland Baltimore, Baltimore, Maryland, United States
- Kuscu, Canan, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Kuscu, Cem, The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Bardhi, Elissa, University of Maryland Baltimore, Baltimore, Maryland, United States
- Eason, James D., The University of Tennessee Health Science Center, Memphis, Tennessee, United States
- Maluf, Daniel G., University of Maryland Baltimore, Baltimore, Maryland, United States
- Gallon, Lorenzo G., Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Mas, Valeria R., University of Maryland Baltimore, Baltimore, Maryland, United States
Background
FSGS, characterized by proteinuria and podocyte injury, is one of the leading causes of end stage renal disease. However, pathogenesis is poorly understood. This study identified cell-population changes, cell-cell interactions, and cell-type specific injury pathways contributing to FSGS recurrence in kidney allografts.
Methods
Single nuclei RNA-seq was performed on allograft biopsies showing normal histology (N=4) and FSGS-related glomerular damage (first (T1) N=3 and second recurrence (T2) N=2). Downstream analyses were done using UMAP, gene and pathway enrichment, and intra- and inter-cluster comparative transcriptomics.
Results
40,078 single nuclei partitioned into 17 clusters (Fig.1A). Proximal tubular cluster 1 was most abundant in normal allografts (21.02%) and diminished in T1 (16.92%) and T2 (15.50%), likely due to apoptosis. Two distinct podocyte clusters (POD1-2) were identified (Fig.1A). Despite shared canonical cell markers (Fig.1B), 516 and 222 DEGs were identified in POD2 vs POD1 at T1 and T2, respectively, indicating phenotype heterogeneity. POD1 was enriched in Wnt signaling and actin filament pathways whereas POD2 was enriched in ECM accumulation, epithelial cell differentiation, and cell-cell adhesion pathways. We identified 8 immune clusters, of which T memory cells were increased in FSGS allografts (T1: 26.87%; T2: 35.74%) compared to normal (4.75%) (Fig.1C). Ligand-receptor analysis revealed proinflammatory signals transmitted between podocytes and immune cells.
Conclusion
FSGS is characterized by a complex cellular and transcriptomic landscape, leading to kidney injury. T1 and T2 interventions require a more targeted approach based on their unique cell-type specific molecular injury pathways.
Funding
- NIDDK Support