Mr Benjamin Adams1,2,3, Dr ETHAN LEVITCH1, Dr XIANGJU WANG1,2, Dr ANDREW KASSIANOS1,2,3, Prof HELEN HEALY1,2,3, Prof CHANGSEONG KIM1,2,4,5
1Pathology Queensland – Conjoint Internal Medicine Laboratory, Brisbane, Australia, 2RBWH – Kidney Health Service, Herston, Australia, 3UQ – Kidney Health Service, St Lucia, Australia, 4Chonnam National University Hospital, Gwangju, Republic of Korea, 5Chonnam National University Medical School, Gwangju, Republic of Korea
Biography:
Benjamin Adams is a PhD student (post-confirmation) at the Conjoint Kidney Research Laboratory, Queensland Health – located at the QIMR Berghofer Medical Research Institute. Ben has significantly contributed to the fields of nephrology, with recent publications examining the role of extracellular vesicle-mediated ferroptotic death signalling in AKI-to-CKD transition (Wang et al, Redox Biol, 2024) and co-first author review defining the mechanisms of tubular senescence in CKD (Giuliani et al, Frontiers, 2024). Ben’s PhD research is focussed on establishing multi-omics platforms for understanding cell-cell communication between kidney and immune cell populations and the therapeutic potential of check-point targeting in disease progression.
Aim:
To resolve spatially distinct molecular signatures that map to functional decline in IgA nephropathy (IgAN).
Background:
IgAN is the most prevalent primary glomerulonephritis in Australia and a leading cause of chronic kidney disease (CKD). Although MEST-C scoring provides histological classification, it lacks sensitivity in predicting clinical outcomes, as patients with similar scores may follow divergent disease trajectories. We used high-resolution spatial transcriptomics to identify segment-specific molecular changes associated with kidney function loss in IgAN.
Methods:
Frozen kidney biopsies from individuals diagnosed with IgAN and low MEST-C scores (<1) were stratified into Group 1 (preserved kidney function, eGFR≥60 mL/min/1.73m², n=6) and Group 2 (CKD, eGFR<60, n=6). Control tissue (n=4) was obtained from histologically healthy regions of tumour nephrectomies. Spatial gene expression was performed on the Xenium platform (10x Genomics), targeting ~400 transcripts at subcellular resolution. Analytical workflows included cell-type deconvolution, spatial clustering and neighbourhood interaction mapping.
Results:
Transcriptionally distinct tubular epithelial segments and immune cell populations were resolved within healthy and diseased tissue. Group 2 IgAN biopsies exhibited enriched proinflammatory and pro-fibrotic transcriptional signatures in specific cell-types compared to group 1 and healthy tissue. Proximal tubules showed elevated PDGFRB, CFB, and S100A1 expression, while distal tubules expressed higher levels of MEST, ACTG2, and CFB. Endothelial cells expressed PDGFRA/B, CAV1, and CD34, and fibroblasts were enriched for CXCL9, CCL5, and CCL19. Neighbourhood analysis revealed spatial clustering of plasmacytoid dendritic cells (pDCs) with injured tubular epithelium in Group 2, suggesting pDC-driven paracrine segment specific signalling.
Conclusions:
Spatial transcriptomics uncovers segment-specific proinflammatory signatures in low MEST-C score IgAN with kidney function loss. These molecular markers may serve as prognostic indicators and targets for precision therapeutics.