Abstract: FR-PO1199
Tumor Necrosis Factor (TNF)α-Triggered Bone Marrow Alterations Fuel CKD Progression
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
- Jimenez Uribe, Alexis P., Rush University, Chicago, Illinois, United States
- Spear, Ryan, Rush University, Chicago, Illinois, United States
- Cao, Yanxia, Rush University, Chicago, Illinois, United States
- Mangos, Steve, Rush University, Chicago, Illinois, United States
- Vincenti, Flavio, University of California San Francisco, San Francisco, California, United States
- Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States
- Hahm, Eunsil, Rush University, Chicago, Illinois, United States
Background
Immune dysregulation contributes to the pathogenesis of CKD. Altered bone marrow (BM) hematopoiesis is commonly observed in CKD-associated conditions, such as diabetes, cardiovascular disease, and aging. Soluble urokinase plasminogen activator receptor (suPAR), a key mediator associated with glomerular damage, is primarily produced by BM-derived immature myeloid cells in mice. However, the role of BM dysfunction in CKD progression has not been studied in humans. We examined how inflammation-induced BM alterations contribute to CKD progression.
Methods
BM aspirates from CKD patients were analyzed using ELISA, multiplex cytokine assays, multicolor flow cytometry, and scRNA sequencing. To mimic CKD patient BM alterations, in vitro myelopoiesis assays were conducted under TNFα exposure. Cellular and molecular changes were assessed via ATAC-seq, RNA-seq, metabolic assays, flow cytometry, and cytokine analysis. We tested the in vivo effect of TNFα blockade and co-injection of TNFα with IFNγ in mice. We also measured TNFα levels in three different mouse models of proteinuria and in suPAR-deficient mice. Secreted factors from TNFα-driven, functionally altered myeloid cells were tested for their impact on renal function using high-throughput immunofluorescence assays on cultured podocytes and filtration function assays in zebrafish.
Results
BM from CKD patients exhibited elevated TNFα and suPAR levels, along with inflammatory transcriptomic profiles in monocytic cells. TNFα-driven myelopoiesis induced altered monocytic cells resembling those in CKD patients. These cells displayed increased metabolic activity, transcriptional and epigenetic reprogramming, and elevated secretion of suPAR and other proinflammatory mediators. These secreted factors caused filtration dysfunction in zebrafish and led to cytoskeletal disarrangement in cultured podocytes. In mice, TNFα exposure during myelopoiesis resulted in increased suPAR levels and proteinuria.
Conclusion
Our study demonstrated that TNFα-driven alterations in BM monocytic cells contribute to glomerular dysfunction through the secretion of suPAR and pro-inflammatory cytokines, suggesting BM dysfunction as a central upstream driver of CKD.
Funding
- NIDDK Support