A circulating glomerular capillary albumin permeability factor (P(alb)) has been implicated in the pathogenesis of focal segmental glomerulosclerosis (FSGS), which recurs in transplanted kidneys. Plasmapheresis for recurrent FSGS may reduce proteinuria and stabilize renal function if instituted early. We performed six plasmapheresis treatments over 2 weeks in eight patients with a history of steroid-resistant idiopathic FSGS in native kidneys for an average of 12 +/- 2.3 months to determine whether treatment would decrease proteinuria or stabilize renal function. P(alb) was measured before and after plasmapheresis, and patients were followed-up for a mean of 29 +/- 4 months after the development of clinical symptoms. Proteinuria decreased in two of eight treated patients, although only transiently in one of the two. P(alb) improved in one of the two responding patients. Both patients with an improvement in proteinuria had stable renal function at last follow-up. In six of eight patients, there was no improvement in proteinuria despite an improvement in P(alb) (P < 0.0001) after plasmapheresis. At last follow-up, renal function was stable in two of the six nonresponding patients, and four of the six had significant progression of renal disease or were receiving dialysis treatments. These studies suggest that plasmapheresis may diminish proteinuria and stabilize renal function in a small minority of patients with steroid-resistant idiopathic FSGS. However, the lack of a relationship between the removal of the circulating permeability factor and the development of remission in these patients suggests that local factors associated with advanced renal injury or systemic factors unrelated to glomerular permeability play a significant role in determining proteinuria at this late stage of the disease.