Serum Syndecan-1 is Associated With Kidney and Cardiovascular Outcomes in Idiopathic Nephrotic Syndrome

Introduction Idiopathic nephrotic syndrome (INS) is associated with important kidney and cardiovascular morbidities. We tested the hypothesis that serum syndecan-1, a marker of endothelial glycocalyx injury, can help identify patients at risk for unfavorable kidney and cardiovascular outcomes. Methods We included 348 children and adults with INS (n=35 unbiopsied, n=141 minimal change disease [MCD] and n=172 focal segmental glomerulosclerosis [FSGS]) from the NEPTUNE cohort and 34 healthy participants (n=22 adults, n=12 children). We measured baseline serum syndecan-1 levels using an enzyme-linked immunosorbent assay (ELISA), and evaluated their relationship with kidney and cardiovascular outcomes. We performed in vitro studies to test whether INS sera and different therapeutics may alter syndecan-1 expression in human glomerular endothelial cells (GEnC). Results Serum syndecan-1 was higher in patients with INS compared to controls; and was also high in ∼1/3 of patients without proteinuria or with sub-nephrotic proteinuria. Patients receiving steroids, regardless of disease activity, showed higher syndecan-1 than those off immunosuppression. Syndecan-1 was higher in proteinuric patients with MCD than in FSGS. At time of serum collection, syndecan-1 modestly correlated with proteinuria but not with kidney function. In longitudinal analyses, serum syndecan-1 associated with the composite of 40% decline in kidney function or kidney failure and with dyslipidemia. In cultured GEnC, INS sera in relapse, compared to control, increased syndecan-1 expression, and this was partially or fully mitigated when dexamethasone or metalloprotease inhibitor were added, respectively, to culture media. Conclusions Baseline serum syndecan-1 is associated with unfavorable kidney outcomes and cardiovascular risk factors in INS.