They were resistant to a standard course of glucocorticoids and had either been treated unsuccessfully with mycophenolate mofetil, azathioprine, cyclosporine, or tacrolimus in the past. Patients, 2-41 years of age, with biopsy-confirmed primary FSGS and calculated GFR >40 mL/min/1.73 m 2, were eligible to participate in the FONT study. In this report, we summarize the kidney function outcomes at follow-up after completion of the Phase I study to obtain preliminary data about the legacy effect of these two drugs, namely their capacity to alter the natural history of the disease in children and young adults with refractory primary FSGS. The main side effects of rosiglitazone are edema, anemia, congestive heart failure and fractures the most serious adverse events related to adalimumab use are infections and malignancy. Rosiglitazone is prescribed to children and adults with type 1 and type 2 diabetes, while adalimumab is utilized in patients with rheumatoid arthritis and inflammatory bowel disease. The first two agents selected for testing were rosiglitazone, a peroxisome-proliferator activated receptor-γ, and adalimumab, a human monoclonal antibody to tumor necrosis factor-α. The primary purpose of the first portion of the Novel Therapies for Resistant FSGS (FONT) study is to evaluate the safety, tolerability, and pharmacokinetic characteristics of novel pharmacological agents that may be antifibrotic and renoprotective. There is an urgent need to develop new strategies to delay or prevent loss of renal function in this patient cohort. Patients who are resistant to corticosteroids and other immunosuppressive medications are at substantial risk of progression to chronic kidney disease (CKD) stage V. The cause of this glomerulopathy remains unknown and there are no proven treatments that consistently induce complete remission of proteinuria. It usually presents with isolated proteinuria or overt nephrotic syndrome in both pediatric and adult patients. Primary focal segmental glomerulosclerosis (FSGS) is increasing in frequency throughout the world. Based on this proof-of-concept preliminary study, we recommend long-term follow-up of patients enrolled in clinical trials to ascertain a more comprehensive assessment of the efficacy of experimental treatments. Nearly 50% of patients with resistant FSGS who receive novel antifibrotic agents may have a legacy effect with delayed deterioration in kidney function after completion of therapy. A similar percentage of patients, 71% and 56%, in the rosiglitazone and adalimumab cohorts, respectively, had stabilization in GFRe, defined as a reduced negative slope of the line plotting GFRe versus time without requiring renal replacement therapy after completion of the FONT treatment period (P = 0.63). The observation period pre-FONT was 18.3 ± 10.2 months and 16.1 ± 5.7 months after the study. Resultsġ9 patients completed the 16-week FONT treatment phase. The change in GFRe per month prior to entry and after completion of the Phase I trial was compared. MethodsĢ1 patients - 12 males and 9 females, age 16.0 ± 7.5 yr, and estimated GFR (GFRe) 121 ± 56 mL/min/1.73 m 2 - received adalimumab (n = 10), 24 mg/m 2 every 14 days or rosiglitazone (n = 11), 3 mg/m 2 per day for 16 weeks. We present outcomes of follow-up after a Phase I trial of adalimumab and rosiglitazone, antifibrotic drugs tested in the Novel Therapies in Resistant FSGS (FONT) study. Antifibrotic agents may slow or halt this process. Patients with resistant primary focal segmental glomerulosclerosis (FSGS) are at high risk of progression to chronic kidney disease stage V.
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