A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues

Primary focal segmental glomerulosclerosis (FSGS) is one of the major causes of steroid-resistant nephrotic syndrome, and renal prognosis in patients with steroid-resistant FSGS is poor. It has been long speculated that a circulating permeability factor should be implicated in the pathogenesis of the disease because a substantial portion of the patients with primary FSGS experience recurrence shortly after transplantation. Although molecules such as cardiotrophin-like cytokine 1 (CLC-1) and anti-CD40 antibody have been proposed to be potential circulating permeability factors, a definitive factor remains to be discovered. Soluble urokinase-type plasminogen activator receptor (suPAR) has attracted substantial attention and garnered scrutiny by renal researchers since Reiser's group suggested that it was linked to the pathogenesis of primary FSGS and that it might be useful as a diagnostic biomarker. A number of different cohort studies have shown that serum suPAR levels are negatively associated with renal function and can scarcely differentiate FSGS from the other glomerular/renal diseases. In contrast to initial studies, several in vivo studies investigating the effects of forced suPAR upregulation could not show the induction of proteinuria or podocyte injury. Currently it is suggested that a different form of suPAR, which cannot be measured by presently available enzyme-linked immunosorbent assay, might be the culprit; however, it remains to be determined whether this is the case. Because a circulating permeability factor might be a useful biomarker for diagnosing FSGS as well as a potent therapeutic target for primary and recurrent FSGS, further dedicated work will be needed.