Bone marrow from focal segmental glomerulosclerosis displays activation of inflammatory pathway.

Circulating factors resulting from immune dysfunction have been proposed as one of the causes for increased risk of graft loss associated with recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplant. However, the precise identity of the circulating factors and their sources remain incompletely characterized. In vivo studies in mouse models have implicated a role for immature bone marrow cells in the development of FSGS. Using single-cell RNA sequencing we have profiled >50,000 cells from bone marrow of FSGS patients with or without recurrence after kidney transplant and controls including healthy individuals and patients with end-stage renal disease due to non-FSGS causes. Bone marrow mononuclear cells from patients with recurrence of FSGS after transplant display an inflammatory phenotype with activation of cytokine and interferon signaling in neutrophils, T cells and B cells. We also observe a dramatically depleted B cell population in R-FSGS patients. Conditioned media from BMNCs of R-FSGS patients have higher levels of pro-inflammatory cytokine MIP-1/CCL3, reduced anti-inflammatory chemokine CCL22 and cause injury in a human podocyte cell culture model. Our studies provide evidence for the role of bone marrow cells in FSGS associated inflammatory milieu and elucidate the transcriptional changes associated with the disease.