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Kidney Week

Abstract: SA-PO1004

Altered Bone Marrow Myelopoiesis Contributes to Renal Injury

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Spear, Ryan, Rush University Medical Center, Chicago, Illinois, United States
  • Xu, Yan, Rush University Medical Center, Chicago, Illinois, United States
  • Vincenti, Flavio, University of California San Francisco, San Francisco, California, United States
  • Cao, Yanxia, Rush University Medical Center, Chicago, Illinois, United States
  • Mangos, Steve, Rush University Medical Center, Chicago, Illinois, United States
  • Reiser, Jochen, Rush University Medical Center, Chicago, Illinois, United States
  • Hahm, Eunsil, Rush University Medical Center, Chicago, Illinois, United States
Background

Altered hematopoiesis in bone marrow (BM) is commonly found in diverse disease conditions associated with CKD, including infection, chronic inflammation, diabetes, CVD, cancer and aging. However, the BM-kidney axis is poorly understood. Here, we tested if inflammatory signals alter BM myelopoiesis leading to renal injury.

Methods

We explored the phenotypic changes of BM components in renal disease by collecting BM aspirates and plasma from CKD patients and healthy donors. We used an in vitro differentiation system to examine how inflammatory signals affect myelopoiesis and cellular functions. Briefly, human CD34+ hematopoietic stem cells (HSC) were isolated from healthy donors and cultured in myeloid expansion media. TNFα was added to mimic inflammatory conditions. Cells and supernatants were subjected to Seahorse, flow cytometric and secretome analyses. The link between BM alteration and renal injury was tested in vivo using two animal models.

Results

CKD patients have high levels of TNFα and suPAR in both plasma and BM, indicative of chronic inflammation. These patients show myeloid-biased hematopoiesis and an increase in inflammatory CD14+CD16+ BM monocytes expressing uPAR. Consistently, myeloid-lineage differentiation assays showed that TNFα skews HSC differentiation towards monocytic lineage at the expense of granulocytes. Along with altered myelopoiesis, TNFα markedly increases uPAR expression, suPAR secretion and promotes production of proinflammatory cytokines including TNFα, IL-8 and IL-6. Additionally, TNFα stimulates monocyte subsets to become metabolically active. Soluble factors from TNFα-driven myeloid cells cause filtration dysfunction in a transgenic zebrafish functional assay. Injecting mice with TNFα and IFNγ (essential for myelopoiesis) leads to significantly elevated ACR, BUN and suPAR levels, along with an increase in uPAR expressing CD11b+ BM myeloid cells, suggesting that TNFα contributes to renal injury by altering BM.

Conclusion

Our findings suggest that TNFα reprograms BM myelopoiesis. Renal injury results from the generation of metabolically active myeloid cells that secrete proinflammatory cytokines and soluble permeability factors. These observations provide important groundwork for the exploitation of the BM-kidney axis as a novel therapeutic target for immune-mediated nephrotic syndrome currently categorized as ‘idiopathic’.