Focal Segmental Glomerulosclerosis (FSGS) in Children and Young Adults Interventional Study

• Ancillary Study Policies
• Steroid-Resistant FSGS Nephrotic Syndrome
• Prevalence and Treatment
• Study Description
• http://www.fsgstrial.org

Steroid-Resistant FSGS Nephrotic Syndrome

Children and young adults with FSGS nephrotic syndrome have large amounts of protein in the urine (proteinuria), which is the result of tissue degeneration and scarring that occurs in the kidney's glomeruli, tiny clusters of looping blood vessels that filter the blood. The degeneration and scarring are characteristically limited to one part of the glomerulus and to a minority of glomeruli in the affected region. Non-selective proteinuria is both a valuable surrogate marker for measuring the severity of injury to the glomeruli and a risk factor for progressive loss of kidney function.

Symptoms of nephrotic syndrome include retention of fluid in body tissues (edema), retention of fluid in the abdominal cavity (ascites), a high level of blood lipids (hyperlipidemia), and formation of blood clots (thromboemboli). Most pediatric patients have renal biopsy findings consistent with the diagnosis of minimal change disease. Typically, these patients will have remission of clinical symptoms after treatment with a course of high-dose prednisone, and they rarely develop progressive disease that leads to end-stage renal disease (ESRD) and kidney failure.

However, a sub-group of nephrotic children and young adults have steroid-resistant or steroid-dependent nephrotic syndrome, and renal biopsies show evidence of FSGS. Localization of the gene for this rare, inherited type is lq25-q31. The long-term prognosis for this sub-group is poorer because no satisfactory treatment exists for their condition.

First described in 1957, FSGS is a common, irreversible disease characterized by the presence of areas of mesangial sclerosis in some glomeruli. Although often secondary to other disorders such as HIV nephropathy, heroin use, or certain malignancies, FSGS also appears as a primary, idiopathic condition that is typically diagnosed on renal biopsy of nephrotic patients whose nephrotic syndrome has failed to respond to steroid therapy. The primary form of FSGS is more common among children and young adults; secondary forms are more common among older adults. FSGS is also one of the most common kidney diseases to recur after a kidney transplant, and it often causes allograft injury (in 20% percent to 30% of patients) or graft loss (in 40% to 50% of patients).

Prevalence and Treatment

The disease appears to be more prevalent and more severe in African-American and, perhaps, in Hispanic-American children. Although steroid therapy is commonly used in the treatment of children with FSGS, approximately 75 percent of patients do not respond to therapy, relapse while on therapy, or relapse rapidly when therapy is stopped. The overall outcome remains unpredictable, with some patients progressing to ESRD within a period of two years, while others reach that point after an average of ten years. In some children the heavy proteinuria may improve with steroid therapy, but at the cost of significant adverse effects.

Converting enzyme inhibitors

Immunomodulation agents-cyclophosphamide and chlorambucil

The immunomodulatory agents, cyclophosphamide and chlorambucil, have been used for treatment of FSGS for several decades. These agents have been studied in several clinical trials. A recent meta-analysis summarizing experience with cyclophosphamide and chlorambucil (Latta et al., Pediatric Nephrology 16:271-282, 2001) notes an overall increased rate of relapse-free survival with increasing doses of either agent. Overall, however, the complication rate with these agents is not insignificant, response rates are not satisfactory, and even among patients who respond, a substantial portion does not remain in long-term remission. Some nephrologists view results with cyclosporin to be more promising, although the overall experience is not extensive, and small, randomized trials have not established it as having an advantage over cytotoxic agents.

A task force to gather information on the criteria for, and the nature of, interventions for a clinical trial was convened in November 2000 by the NIDDK and the American Society of Pediatric Nephrology. This initiative is based on recommendations of the task force.

Study Description

No current treatment for nephrotic syndrome caused by FSGS is completely satisfactory. Many children and young adults with this condition are at high risk for kidney failure because they are resistant to standard therapy with prednisone. The NIDDK has formed a collaborative network of research centers that will test the effects of treatment with cyclosporine to treatment with mycophenalate mofetil combined with oral pulse dexamethasone. Efficacy will be assessed in terms of induction of remission of proteinuria after 52 weeks of treatment and sustained remission after 26 weeks off treatment.

Approximately 500 participants, ages 2 to 35, will be recruited for the 5-year study, which will begin in spring 2004. The clinical sites are State University of New York, Stony Brook; Montefiore Medical Center; Seattle Children's Medical Center; Medical City Dallas Hospital; and the University of North Carolina. The Cleveland Clinic is the data-coordinating center, and NephCure will fund ancillary studies. This clinical trial is currently in the planning stages and is scheduled to end in 2007.

The NIDDK-sponsored network was formed through a cooperative agreement, an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during performance of the trial.