Circulating permeability factor suPAR: from concept to discovery to clinic

Kidney filtration functions through a hydrostatically driven multicellular barrier that includes visceral epithelial cells termed podocytes. These cells have delicate foot processes by which they ensure proper generation of urine. Most forms of chronic kidney disease start with disruption of podocytes, allowing for a breakdown of kidney barrier function and loss of plasma proteins from the blood into the urine (proteinuria). A classic podocyte disease is focal segmental glomerulosclerosis (FSGS) which progresses from podocyte injury to chronic kidney disease (CKD) and end-stage renal disease (ESRD) in a well-defined histopathological pattern. FSGS can recur after kidney transplantation in 30% or more cases, affecting both children and adults with rapid disease onset. This scenario has led credence to the concept that FSGS is caused by one or more circulating blood factor (s) that in turn cause podocyte injury. Decades of search for viable circulating permeability factor candidates have sparked research in this area. Recently, soluble urokinase plasminogen activator receptor (suPAR) was identified in a majority of patients with FSGS as a soluble factor that acts through binding to and activating podocyte beta 3 integrin. These observations show promise for novel therapeutic development to eliminate a portion of FSGS cases.