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

Some children and young adults with nephrotic syndrome caused by focal segmental glomerulosclerosis (FSGS) are at high risk for kidney failure because they are resistant to or dependent on standard therapy with prednisone. No current treatment for this condition is satisfactory. The NIDDK has formed a collaborative network of research centers that will test the effects of cyclosporin or novel immune system modulation agents on reduction of proteinuria in these patients.

Approximately 400 children and young adults will be enrolled in the five-year study. 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 data-coordinating center is the Cleveland Clinic, and NephCare will perform ancillary studies.

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.

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 FSGS 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 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).

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.

A number of strategies have been employed to treat FSGS. Two current therapies are

• Converting enzyme inhibitors
• Immunomodulation agents-cyclophosphamide and chlorambucil

Converting enzyme inhibitors (CEIs) are one established strategy to slow the progression of certain forms of kidney disease. However, the effects of CEIs have not been examined in children with FSGS, and in adults, the number of patients studied has been too small to allow meaningful subgroup analyses. Nonetheless, because the drugs are well tolerated and frequently result in some reduction in proteinuria, many nephrologists consider use of a CEI to be standard care, at least for patients who have both proteinuria and hypertension.

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 cyclophospahmide and chlorambucil (Latta et al. Pediatric Nephrology 16:271-282) 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 do 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.

The NIDDK multi-center collaborative will consist of regional coordinating centers and a data-coordinating center formed through a cooperative agreement, an assistance mechanism in which substantial NIDDK scientific and programmatic involvement is anticipated during performance of the trial. Because the number of patients with FSGS who are followed at any one medical institution is likely to be insufficient to meet the recruitment goal for an individual regional clinical coordinating center, the multi-center collaborative will have a central institution coordinating the recruitment, intervention, and follow-up of patients entered into the trial from other medical organizations and individual physicians.