Focal segmental glomerulosclerosis (FSGS) is associated with circulating permeability activity (Palb) and recurs after transplantation in about 30% of patients. The FS permeability factor (FSPF) consists of anionic low-molecular-weight protein(s) that might be excluded by the anionic filtration barrier. We postulated that FSPF may interact with sugars of the glycocalyx, and we tested its affinity for sugars using column chromatography. FSPF showed high affinity for galactose; Palb activity was absent from unbound material and present in eluate after dialysis to remove galactose. In parallel studies, Palb activity of serum was lost after adding galactose > or = 10(-12) M. To determine whether galactose also abolishes plasma Palb activity in vivo, a patient with posttransplant FSGS was given galactose and serum samples were collected. Intravenous infusion of galactose decreased Palb from 0.88 before infusion to undetectable levels postinfusion and at 48 hours. Oral galactose diminished Palb activity; Palb reached a nadir after 2 weeks and remained low for at least 4 weeks after galactose was discontinued. We conclude that FSPF has high affinity for galactose based on chromatography. Additionally, galactose inactivates FSPF and may lead to its clearance from plasma. The interaction between FSPF and glomeruli may depend on FSPF binding to galactose, and the FSPF-galactose complex may be susceptible to uptake by galactose-binding proteins and to catabolism. We propose testing galactose as a novel nontoxic therapy for nephrotic syndrome in FSGS to determine whether galactose slows progression and whether pretransplant therapy decreases rates of recurrence and graft loss.