Abstract: SA-OR048
Spatial Transcriptomics Reveals Sparsentan-Associated Remodelling of Complement-Active Renal Niches in IgAN
Session Information
- Glomerular Diseases: Clinical Trial Results
October 24, 2026 | Location: Mile High Ballroom 4A, Convention Center
Abstract Time: 04:50 PM - 05:00 PM
Category: Glomerular Diseases
- 1402 Glomerular Diseases: Clinical, Outcomes, and Therapeutics
Authors
- Kepple, Jessica, University of Oxford, Oxford, England, United Kingdom
- Selvaskandan, Haresh, University of Leicester, Leicester, England, United Kingdom
- Keung, Jenna, European Bioinformatics Institute, Cambridge, England, United Kingdom
- Boys, Charlotte May, University of Leicester, Leicester, England, United Kingdom
- Smith, Hannah Marie, University of Leicester, Leicester, England, United Kingdom
- Barratt, William Alfred, University of Leicester, Leicester, England, United Kingdom
- Ju, Wenjun, University of Michigan, Ann Arbor, Michigan, United States
- Nair, Viji, University of Michigan, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan, Ann Arbor, Michigan, United States
- Komers, Radko, Travere Therapeutics Inc, San Diego, California, United States
- Mercer, Alex, Travere Therapeutics Inc, San Diego, California, United States
- Hendry, Bruce M., Travere Therapeutics Inc, San Diego, California, United States
- Cheung, Chee Kay, Leicester General Hospital, Leicester, England, United Kingdom
- Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
- Saez-Rodriguez, Julio, European Bioinformatics Institute, Cambridge, England, United Kingdom
- Barratt, Jonathan, University of Leicester, Leicester, England, United Kingdom
- Bull, Katherine R., University of Oxford, Oxford, England, United Kingdom
Background
The clinical trial SPARTAN (NCT04663204) evaluates the therapeutic sparsentan (SPAR), a dual endothelin and angiotensin receptor antagonist, in patients with IgA nephropathy (IgAN), using a multi-omic approach to identify novel disease biomarkers. Proteomic analysis of urinary and plasma biomarkers showed reductions in inflammatory markers, including complement components, after SPAR treatment (Ju, W; SPARTAN Study Abstract). Renal cell-specific mechanisms and tissue niches underlying changes in complement activation remain unclear, including whether treatment alters inflammatory cell infiltration, compartment-specific injury, or complement-active cellular niches.
Methods
We performed high-resolution spatial transcriptomic profiling using the Xenium platform on formalin-fixed, paraffin-embedded (FFPE) renal biopsies from SPARTAN-enrolled IgAN patients, obtained before or after SPAR treatment. Samples were analysed using a human 5,000-gene panel and a supplementary custom immune-focused panel. Comparative bioinformatic analyses were conducted to assess changes in cellular composition, differential transcriptional programmes, and spatial niche interactions in pre- and post-treatment renal biopsies.
Results
SPAR treatment attenuated haemodynamic stress and complement-associated transcriptional programmes. Spatial profiling identified hyperactive alternative complement niches enriched in fibroblasts, proximal tubular cells, and parietal epithelial cells, consistent with interstitial remodelling and glomerular stress responses. These hyperactive states were associated with increased fibroblast clustering, greater T-cell proximity, and reduced tubular adjacency, forming dense stromal-inflammatory microenvironments attenuated by SPAR treatment. In glomeruli, alternative complement activity was highly enriched in discrete niches of parietal epithelial cells and podocytes associated with extracellular matrix remodelling and dysregulated immune signalling, which were reduced with SPAR treatment.
Conclusion
Our findings suggest that SPAR modulates complement-associated injury indirectly by reducing the inflammatory and fibrotic microenvironments that sustain alternative complement activation. Spatially organised fibroblast-rich complement niches may represent key tissue compartments linking complement urine biomarkers to progressive renal remodelling in IgAN.
Funding
- Commercial Support – Travere Therapeutics