Is there clinical value in measuring suPAR levels in FSGS?

FSGS is a podocyte-derived glomerular disease characterized by marked proteinuria, often coupled with steroid resistance, hypertension, and high probability for progression to renal failure. It is a heterogeneous disorder that can present as a primary disorder of unknown etiology. A number of genetic mutations in various proteins have been linked to the development of FSGS. Finally, the glomerulopathy can represent an adaptive response that is secondary to a variety of insults such as HIV infection, obesity, or reduced renal mass (1). Moreover, the disease recurs in approximately 30% of patients who receive a kidney transplant. Recent findings suggest that increased levels of circulating soluble urokinase-type plasminogen activator receptor (suPAR) may trigger the podocytopathy in the majority of patients with primary FSGS. In this issue, Bock et al. (2) report findings in 99 pediatric patients at a single center and conclude that serum suPAR levels are not increased in those with primary FSGS compared with children with non-FSGS glomerular disease, nonglomerular disease, or healthy controls. The term permeability refers to the effects of the factor causing leakiness of the filter which can occur before and after kidney transplantation. Rodents injected with whole or fractionated serum from patients with recurrent FSGS develop proteinuria (3). Sera from patients with FSGS increase albumin permeability in isolated glomeruli and transient nephrotic syndrome has been transmitted to a newborn from a mother with FSGS [reviewed by Sharma et al. (3)]. The presence of permeability factors has provided the rationale to treat FSGS with plasmapheresis (3). Current candidate molecules are cardiotrophin-like cytokine-1 (which was proposed as a putative FSGS permeability factor), hemopexin, and vascular endothelial growth factor [reviewed by McCarthy et al. (4)]. Studies from our laboratory suggest that the permeability factor in both native and recurrent FSGS is suPAR. The identification of suPAR as a FSGS factor might appear counterintuitive to some because suPAR levels are elevated in other diseases, including cancer and infection, that do not routinely present with proteinuria. In addition, some patients present with normal suPAR serum levels and still develop recurrent FSGS (5,6). suPARis the cleavedmoleculederived fromUrokinasetype plasminogen activator receptor (uPAR), which is a glycosyl-phosphatidylinositol anchored membrane protein present on multiple cells, including podocytes. Both uPAR and suPAR activate avb3 integrin signaling (6,7). Using multiple animal models, we showed that acute induction of suPAR in uPAR null mice as well as chronic suPAR overexpression of the suPAR variant (GenBank accession number BC010309) in wild-type mice caused features of FSGS such as foot process effacement, proteinuria, and segmental lesions, all of which could be ameliorated with the addition of a uPAR-specific Ab or by expression of suPAR deficient in integrin b3 binding (6). Using a commercially available ELISA assay kit, we demonstrated that suPAR levels were increased in two thirds of pediatric and adult patients with biopsyprovenFSGS, includingbothnativeandrecurrentFSGS cases (n578) (6). We confirmed these findings in patients with FSGS from two well characterized cohorts: the FSGS Clinical Trial (FSGS CT) (n570, pediatric and adult patients, eGFR.40 ml/min per 1.73 m2) and the PodoNet European FSGS consortium (n594, pediatric patients, normal eGFR) (8). Using 3 ng/ml as a cut-off value, we demonstrated that suPAR levels were elevated in 84% and 55% of patients in the two cohorts, respectively. Importantly, the elevation of suPAR in these FSGS patients was not related to inflammation because concurrent C-reactive protein (CRP) levels were not elevated. Huang et al. also showed elevation of suPAR in the majority of serum samples from adult patients with primary FSGS in a cohort from Beijing (9). Most recently, Franco Palacios et al. suggested the use of urinary suPAR as pretransplantation biomarker for recurrent FSGS (10). The hypothesis that circulating suPAR drives the disease in a subset of FSGS is directly challenged by Bock et al. (2) in this issue of CJASN. They report that suPAR levels were not significantly different in childrenwith primary FSGS (n520), non-FSGS glomerular disease (n5240), nonglomerular CKD (n526), and healthy controls (n529). It should be noted that although the authors assert that they performed the first evaluation of suPAR in pediatric patients with FSGS, 42 of the 70 patients enrolled in the FSGS CTwere aged ,18 years and were included in the random subset selected for assay of plasma suPAR levels. Moreover, the PodoNet cohort included children and adolescents with FSGS (8). However, it is worth exploring potential differences that might explain the disparate *Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Pediatrics, New York University, New York, New York; and Department of Medicine, Rush University, Chicago, Illinois