Abstract: FR-PO1220
Transcriptomics Linking Complement and Proteinuric CKD
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Fu, Vienna, University of Toronto, Toronto, Ontario, Canada
- Khandelwal, Priyanka, The Hospital for Sick Children, Toronto, Ontario, Canada
- Hartman, John R., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
- Licht, Christoph, The Hospital for Sick Children, Toronto, Ontario, Canada
Background
Chronic kidney disease (CKD) is a major healthcare challenge with limited available therapeutic interventions. Despite its diverse etiologies, CKD is characterized by shared pathological mechanisms, one of the most prominent being proteinuria — a key driver of glomerular and tubulointerstitial (TI) injury. Importantly, the specific mechanisms involved in proteinuria-mediated renal damage are not fully known. Recent evidence suggests that the complement system, a component of innate immunity, may represent a key common pathway involved in the progression of proteinuric CKDs, regardless of the underlying cause. During proteinuria, circulating complement proteins leak into the tubular space, causing tubular damage. Additionally, it is speculated that during proteinuria, tubular epithelial cells synthesize complement proteins that become locally activated, also contributing to tubular damage; however, further investigation is required to confirm this concept. Therefore, we aimed to explore the link between intrarenal complement and proteinuric CKD. We hypothesized that intrarenal complement is a key shared mechanism involved in the progression of proteinuric CKD, irrespective of the underlying cause.
Methods
To test this hypothesis, we collaborated with the Nephrotic Syndrome Study Network (NEPTUNE), a multi-center consortium focused on nephrotic syndrome research. Together, we analyzed complement transcripts (C1-C9 and key regulators) and clinical readouts from micro-dissected kidney biopsies from patients with various proteinuric CKDs: focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranous nephropathy (MN), and IgA nephropathy (IgAN).
Results
We have shown constitutive expression of complement in renal compartments with upregulation of complement genes during proteinuric disease, particularly in the TI (p<0.05 across all disease etiologies). Additionally, TI complement expression was shown to be correlated with estimated glomerular filtration rate (eGFR) decline and proteinuria in various proteinuric CKDs.
Conclusion
This study presents evidence linking complement and proteinuric CKD, with a specific emphasis on its role in TI pathology. Ultimately, these findings support the potential use of existing complement blockers as a therapeutic strategy for proteinuric CKDs, regardless of the underlying etiology.
Funding
- Private Foundation Support