Analysis of Single-Nucleus Data Improves Understanding of IgAN

Single-cell data can enhance our understanding of IgA nephropathy (IgAN). In a poster session at ASN Kidney Week 2024 titled Dissecting Deregulated Multicellular Programs in IgA Nephropathy, Charlotte M. Boys and colleagues presented results from an unsupervised exploratory analysis of single-nucleus data from the Omnibus of CElls And Nuclei (OCEAN).

The goal was to study transcriptomic alterations in primary proteinuric glomerular diseases, with an emphasis on IgAN. OCEAN includes the data of 11 living donors from the Michigan Human Kidney Transplant Transcriptomic Atlas study and 120 patients from the NEPTUNE consortium with IgAN, focal segmental glomerulosclerosis (FSGS), minimal change disease, and other kidney diseases.

The researchers generated pseudobulk profiles from OCEAN 10x single-nucleus data for each cell type and sample. They calculated candidate ligand-receptor interactions utilizing LIANA+. They then performed an exploratory data analysis on the pseudobulk profiles and ligand-receptor features using the multicellular factor analysis framework. This resulted in unsupervised “factors” describing transcriptomic heterogeneity across all samples, including living donors.

The factors were associated with clinical metadata and cell type compositional information by analysis of variance post-hoc. Additional analysis centered on factors elucidating patient heterogeneity in IgAN.

The analysis separates transcriptomic alterations in the tubular compartment associated with GFR loss (P<1e-10) and patient age (P<1e-8) from other, more specific, pathological changes. The researchers found additional patterns of transcriptomic dysregulation and cell-cell communication that accounted for heterogeneity in IgAN patient samples. This included a factor associated with parietal epithelial cell expansion and loss of podocytes, along with downregulation of Slit-Robo signaling, which was also seen in FSGS.

In summary, this analysis of single-nucleus data described heterogeneity in IgAN and uncovered pathogenic alterations in the IgAN transcriptome, thus placing them in the larger context of nephrotic syndrome and glomerular disease.

Source: Boys CM, McCown PJ, Eddy S, Kretzler M, Saez-Rodriguez J. Dissecting deregulated multicellular programs in IgA nephropathy. TH-PO532. Abstract of a poster presented at the American Society of Nephrology Kidney Week 2024; October 24, 2024; San Diego, California.