Calcineurin inhibitors are effective therapy for steroid-resistant focal segmental glomerulosclerosis (FSGS) but are associated with significant morbidity and nephrotoxicity. Sirolimus is a novel immunosuppressive agent that is structurally related to tacrolimus but demonstrates no long-term nephrotoxicity. For determination of the efficacy of sirolimus in reducing proteinuria, a prospective, open-label trial was conducted of 21 patients with idiopathic, steroid-resistant FSGS. A complete response was defined as <300 mg protein/24 h after 6 mo, whereas a partial response was defined as a 50% reduction in baseline proteinuria. After 6 mo of therapy, sirolimus induced complete remission in four (19%) of 21 patients and partial remissions in eight (38%). Among sirolimus-responsive patients, 6 mo of therapy decreased proteinuria from a mean of 8.8 ؎ 1.7 to 2.1 ؎ 0.5 g/24 h (P ‫؍‬ 0.0003). In responsive patients, GFR was maintained (45 ؎ 6 versus 47 ؎ 7 ml/min per 1.73 m 2 at 6 mo) throughout the study, whereas nonresponders tended to decrease (31 ؎ 4 versus 28 ؎ 5 ml/min per 1.73 m 2 ). Using dextran sieving analysis, complete or partial response was associated with an increase in the glomerular ultrafiltration coefficient (K f , 7 ؎ 1. versus 8 ؎ 0.9 units at 6 mo; P < 0.05). Glomerular permselectivity and K f tended to decrease in nonresponders (8.2 ؎ 1.9 versus 6.2 ؎ 1.3 units at 6 mo; P ‫؍‬ 0.07). Patients with complete remission had a higher GFR (45 ؎ 6 versus 31 ؎ 4 ml/min per 1.73 m 2 ) at the end of 6 mo compared with nonresponders. In patients with steroid-resistant FSGS, sirolimus reduced proteinuria and glomerular pore size and increased K f in patients with steroid-resistant FSGS.Clin J Am Soc Nephrol 1: 109 -116, 2006. doi: 10.2215/CJN.00120605 P rimary focal segmental glomerulosclerosis (FSGS) is a significant cause of the nephrotic syndrome within adult and pediatric populations (1). Recent epidemiologic studies demonstrated that the incidence of FSGS has increased significantly over the past 2 decades and now accounts for Ͼ35% of all cases of adult-onset nephrotic syndrome (1,2). Black individuals are two-to four-fold more likely to develop FSGS compared with age-matched white individuals and are at increased risk for progression to ESRD (2,3).The pathogenesis of FSGS is unknown, but numerous human and animal model studies suggest that alteration in podocyte structure and function is central to the development of the disorder (4). The de-differentiation and proliferation of podocytes leads to effacement of footplate processes, detachment of podocytes from glomerular basement membranes, and expansion of the mesangial matrix (4 -7). The resulting loss of glomerular barrier function allows for massive proteinuria, sclerosis, and adhesions of the glomerular tuft to Bowman's capsule (8). Other data suggest that cytokines such as TGF-␤ or the presence of circulating vascular permeability factors contribute to footplate effacement and glomerular sclerosis (9,10).Oral steroids remain the primary therapy for ...