Modulation of dead cell disposal and inflammatory signaling as novel approach to peritoneal membrane preservation in dialysis

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Peritoneal dialysis (PD) for renal replacement therapy employs a biologic barrier, the peritoneal mesothelial wall, for clearance of uremic solutes and excess water and electrolytes. Chronic deterioration of peritoneal ultrafiltration capacity, a process that is promoted by hyperosmolar dialysis solutions and infectious peritonitides, limits its use. Peritoneal dialysis fluid induces excess cell death, but knowledge of the underlying pathways is very limited. We recently identified a new profibrotic interaction mechanism of macrophages with mesothelium and detected upregulation of a dead cell disposal (efferocytosis) molecule in protected mice. The present project Aim 1 is to delineate mechanisms of professional and nonprofessional phagocyte efferocytosis in PD. Aim 2 will study cell death, efferocytosis and underlying mechanisms in correlation to outcome in an established PD cohort and prospectively evaluate macrophage and mesothelial cell efferocytosis in incident and stable PD and in acute peritonitis. Aim 3 is to test its modulation as a novel therapeutic intervention strategy in PD associated fibrosis. Improvement of efferocytosis may serve as a new therapeutic angle for preservation of peritoneal function.