Kidney Week

Abstract: FR-PO790

Bone Marrow Inflammation and Alteration Fuel CKD Progression

Session Information

• Glomerular Diseases: Inflammation and Immunology
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Spear, Ryan, Rush University, Chicago, Illinois, United States

Ryan Spear

• Jimenez Uribe, Alexis P., Rush University, Chicago, Illinois, United States

Alexis P. Jimenez Uribe, MS, MSc, PhD, DVM

• Cao, Yanxia, Rush University, Chicago, Illinois, United States

Yanxia Cao, MS

• Mangos, Steve, Rush University, Chicago, Illinois, United States

Steve Mangos, PhD

• Vincenti, Flavio, University of California San Francisco, San Francisco, California, United States

Flavio Vincenti, MD

• Reiser, Jochen, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States

Jochen Reiser, MD, PhD

• Hahm, Eunsil, Rush University, Chicago, Illinois, United States

Eunsil Hahm, PhD

Background

Altered hematopoiesis in the bone marrow (BM) is commonly found in various conditions associated with CKD, including infection, chronic inflammation, diabetes, CVD, cancer, and aging. Our group recently identified BM-derived immature myeloid cells as key contributors to glomerular dysfunction in mice. Despite its potential importance in CKD development, the role of the central immune system, specifically the BM, has not been thoroughly interrogated in humans. Here, for the first time, we examine human BM in CKD and uncover how altered BM myelopoiesis contributes to the progression of CKD.

Methods

BM samples from CKD patients (4 primary and 5 secondary FSGS, 1 non-FSGS) and healthy donors (7) were analyzed. In vitro myelopoiesis was complete using human hematopoietic stem cells. Cellular and molecular characteristics were assessed with flow cytometry, ELISA, scRNA-, RNA- and ATAC-seq. Functional studies included high-throughput IF assays on cultured podocytes and filtration function assays in a transgenic zebrafish model.

Results

CKD patients exhibited significantly elevated levels of TNFα and suPAR, with a myeloid-biased hematopoiesis and increased inflammatory monocytes expressing uPAR. scRNA-seq revealed increased monocyte activation via upregulated genes associated with proinflammatory cytokine and signaling pathways. Consistently, in vitro myelopoiesis demonstrated that TNFα skews hematopoietic differentiation towards activated monocytic lineage cells. These TNFa-driven monocytic subsets exhibited increased uPAR expression, suPAR secretion, and altered transcriptomic, epigenetic, and motif binding profiles. These profiles showed enhanced expression and chromatin accessibility to genes similar to those in patients' BM. Significant cytoskeletal rearrangement was observed in cultured podocytes treated TNFa-induced myeloid cell secreted factors (TIMCSFs) or FSGS patient serum but not by TNFa alone. Similarly, TIMCSFs led to filtration dysfunction in a transgenic zebrafish model.

Conclusion

This study reveals the functional connection between BM myelopoiesis and CKD in humans. Our findings suggest that TNFα, driven by chronic inflammation, plays a key role in altering BM myeloid cells, thereby contributing to glomerular dysfunction in CKD patients. These findings highlight the BM-kidney axis as a potential novel therapeutic target for CKD.

Funding

• NIDDK Support