Circulating soluble urokinase receptor and focal segmental glomerulosclerosis

Background: Clinical observations of rapid proteinuria after kidney transplantation suggest the existence of a causative permeability factor in the circulation of focal segmental glomerulosclerosis (FSGS) patients. Searching for such factor(s) however has been extremely painstaking and extends over the last five decades. We recently identified soluble urokinase receptor (suPAR) as a circulating FSGS factor.

Summary: suPAR represents the soluble form of a glycosylphosphatidylinositol-anchored membrane protein and has been implicated in a number of clinical conditions. With three different rodent models, we showed that acute induction of circulating suPAR could deposit into the glomerulus and then activate podocyte αVβ3 integrin activity; chronic suPAR overexpression caused kidney changes resembling FSGS, which could be ameliorated by suPAR blocking antibody or by expression of suPAR deficient in β3 integrin binding. Analysis of circulating suPAR in four large cohorts of primary FSGS and normal renal average function with more than 300 patients indicates that suPAR level is increased in the majority of FSGS patients. Additionally, circulating suPAR could be removed by plasmapheresis. Removal of suPAR and decreasing podocyte αVβ3 integrin activity is associated with proteinuria remission in recurrent FSGS. suPAR-induced podocyte β3 integrin was observed particularly with FSGS and is independent from inflammation.

Conclusion: suPAR drives αVβ3 integrin signaling in podocytes during FSGS.

Key Message: Circulating suPAR contributes to FSGS. Current ELISA measurements of serum suPAR are handicapped by suPAR's association with GFR and by the lack of detection for aberrant suPAR forms relevant to FSGS. The specificity of ELISA testing can be improved by analysis of the suPAR-αVβ3 integrin signaling axis using cultured human podocytes. The future holds the identification of specific pathological suPAR forms for FSGS and renewed ELISA testing to develop novel therapies of suPAR modification for patients.