To evaluate the safety and efficacy of
sirolimus in treating patients with
focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS,
proteinuria with
protein of 3.5 g/d or greater while on
angiotensin antagonist
therapy, glomerular filtration rate (GFR) of 30 mL/min/1.73 m(2) or greater (>or=0.50 mL/s), and failure to achieve sustained remission with at least 1
immunosuppressive agent. Eligible patients received
sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in
proteinuria, expressed as complete remission (
protein < 0.3 g/d) or partial remission (
protein >or= 50% decrease and <3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline
proteinuria with
protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received
cyclosporine. No patient experienced a complete or partial remission.
Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of
therapy with a greater than 2-fold increase in
proteinuria in 3 patients and (2)
hypertriglyceridemia with
triglyceride levels greater than 1,600 mg/dL (>18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening
proteinuria, the protocol was closed to further recruitment. We conclude that
sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior
cyclosporine therapy.