Circulating suPAR in Two Cohorts of Primary FSGS

Abstract

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsyproven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P,0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Is There Clinical Value in Measuring suPAR Levels in FSGS?

“…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 m 2 ) 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.…”

“…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 CT were 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 findings.…”

Recurrent focal segmental glomerulosclerosis after kidney transplantation

“…suPAR-mediated activation of β3 integrin is the putative mechanism of action of this molecule. A follow-up study reported elevated serum suPAR levels in 55 and 84 % of patients with primary FSGS in two welldescribed cohorts compared to 6 % of controls [38]. Elevated levels of suPAR were noted in patients with an NPHS2 mutation.…”

“…Elevated levels of suPAR were noted in patients with an NPHS2 mutation. In addition, lower levels were associated with male sex and increased estimated GFR [38]. Findings in other cohorts have raised questions about the role of suPAR in the pathogenesis of proteinuria, its ability to discriminate FSGS from other forms of primary glomerular disease, and its predictive value in identifying recurrent disease post-transplant [39][40][41].…”

Soluble Urokinase-Type Plasminogen Activator Receptor in FSGS

“…Several follow-up studies confirmed increased total suPAR serum levels in FSGS, which were validated in patients with normal or mildly reduced renal function compared with other glomerular diseases 5 but not necessarily in advanced renal failure in which suPAR accumulation may occur. 6 Furthermore, it should be noted that in certain recent studies, serum suPAR did not differentiate FSGS from other glomerulopathies in the setting of relatively preserved renal function.…”