Targeting Bone Marrow to Treat Renal Disease

The goal of this project is to explore a role for the bone marrow (BM) immune system in the pathogenesis of idiopathic nephrotic syndrome (NS) and uncover key immune signatures of the disease. Inflammation and immune system activation have long been considered the major culprits of idiopathic NS, yet the underlying mechanisms are still poorly understood. Primary focal segmental glomerular sclerosis (FSGS) is one of the most common causes of non-familial idiopathic NS in adults. While it is often responsive to immunosuppressive therapy, in many cases patients experience a progressive loss of renal function. Moreover, about 30~50% of FSGS cases recur in newly transplanted kidneys. While its incidence keeps rising, there is no cure for FSGS, and current treatment options are non-specific and often cause significant side effects. Thus, there is an urgent need to identify the immune factors and relevant mechanisms that can be targeted therapeutically to treat idiopathic NS such as FSGS and prevent recurrence of the disease. We recently discovered that BM-derived immature myeloid cells are a main source of circulating soluble urokinase receptor (suPAR) and contribute to proteinuric kidney diseases such as FSGS. These findings suggest that the BM is not simply a place for blood cell production, but is also a central and upstream regulator of kidney function by acting as the source of soluble factors such as suPAR. Consistent with results seen in mice, our preliminary data shows that patients with ESRD have high levels of TNFa and suPAR in both plasma and BM, reflecting a status of chronic inflammation. Moreover, these patients exhibit myeloid-biased hematopoiesis and show a robust increase in inflammatory CD14+CD16+ BM monocytes that are found to predominantly express uPAR. In vitro assays show that TNFa skews hematopoietic stem cell (HSC) differentiation towards monocytic lineage cells at the expense of granulocyte production. Along with the altered myelopoiesis, we found that TNFa markedly increases uPAR expression, suPAR secretion, and promotes production of proinflammatory cytokines including TNFa, IL-8, and IL-6. Based on our published and preliminary data, we hypothesize that inflammatory signals alter BM myelopoiesis leading to renal injury in certain forms of glomerular diseases and that this can be treated or reversed by correcting the inflammation-driven BM alteration. To test this hypothesis, we will precisely define the nature of the BM immune alteration in renal disease (Aim 1), determine how the BM immune factors drive renal injury (Aim 2), and test if BM correction improves renal function (Aim 3). Importantly, the identification of immune factors and relevant mechanisms in patients diagnosed with kidney disease will improve the current stratification of the disease and help to develop novel therapies for certain forms of proteinuric kidney diseases currently categorized as ‘idiopathic’.