Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis

Abstract

Focal segmental glomerulosclerosis (FSGS) is a cause of proteinuric kidney disease, compromising both native and transplanted kidneys. Treatment is limited because of a complex pathogenesis, including unknown serum factors. Here we report that serum soluble urokinase receptor (suPAR) is elevated in two-thirds of subjects with primary FSGS, but not in people with other glomerular diseases. We further find that a higher concentration of suPAR before transplantation underlies an increased risk for recurrence of FSGS after transplantation. Using three mouse models, we explore the effects of suPAR on kidney function and morphology. We show that circulating suPAR activates podocyte β3 integrin in both native and grafted kidneys, causing foot process effacement, proteinuria and FSGS-like glomerulopathy. Our findings suggest that the renal disease only develops when suPAR sufficiently activates podocyte β3 integrin. Thus, the disease can be abrogated by lowering serum suPAR concentrations through plasmapheresis, or by interfering with the suPAR–β3 integrin interaction through antibodies and small molecules targeting either uPAR or β3 integrin. Our study identifies serum suPAR as a circulating factor that may cause FSGS.

Recurrent focal segmental glomerulosclerosis after kidney transplantation

“…Wei et al [37] found that suPAR is elevated in nearly two-thirds of patients with primary FSGS and that a higher pre-transplant level correlates with increased risk of recurrence. suPAR-mediated activation of β3 integrin is the putative mechanism of action of this molecule.…”

“…High suPAR levels in the circulation were linked to recurrent FSGS post-transplantation [37]. Podocyte foot process effacement, the initial histological sign of recurrent FSGS, correlates with circulating suPAR levels at the time of diagnosis [42].…”

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…While children typically respond well to steroids and are often treated empirically without a kidney biopsy, those who are steroid-dependent, steroid-resistant and/or frequent relapsers, pose a therapeutic challenge. While the underlying pathophysiology is still being actively investigated, T-cell dysfunction and various permeability factors have been implicated in the pathogenesis [78], [79] and [80]. RTX has been used with some success in children with steroid-dependent idiopathic nephrotic syndrome, as shown in several case reports [81], [82], [83] and [84].…”

uPAR signaling is under par for the podocyte course

“…FSGS commonly recurs after transplantation. Wei et al [7] also found that high concentrations of suPAR before transplantation were associated with increased risk for recurrence of FSGS after transplantation. They next used three mouse models to explore the effects of suPAR on kidney function and morphology.…”

“…Wei et al [7] then introduced the next startling findings regarding uPAR in podocytes. They reported that suPAR, introduced above, is elevated in about two thirds of patients with FSGS, but not in patients with other glomerular diseases.…”