Title: The Focal Segmental Glomerulosclerosis Clinical Trial

PI: Gerald Appel, MD

Focal segmental glomerulosclerosis (FSGS) is a clinical entity with a distinctive

histopathologic appearance. The most common clinical manifestation of this disorder is proteinuria. This lesion may account for 10-20% of cases of idiopathic nephrotic syndrome in children and 35% of cases in adults. In the majority of patients, this lesion is refractory to therapeutic interventions and progression to end stage renal disease is an expected outcome.

Therapeutic interventions for the treatment of FSGS have been widely reported. However, evidence based treatment guidelines have not been developed because of the lack of control studies and the small number of patients included in most reports.

The primary objective is to conduct a multi-center, prospective, randomized trial to compare the effectiveness of a treatment regimen including Cyclosporine-A (CSA) to a regimen including mycophenolate mofetil (MMF) and oral pulse steroids in inducing remission of proteinuria in patients with steroid resistant FSGS. Both of the regimens will also include an ACE inhibitor and alternate day low dose prednisone. On a therapeutic background of alternate day steroids and inhibition of renin angiotensin system, the main research hypotheses are that patients with steroid resistant FSGS who are treated with MMF/oral pulse dexamethasone will have significantly greater proportion with a) remission of proteinuria after 52 weeks on therapy and/or b) remission of proteinuria 26 weeks after withdrawal of therapy when compared to similar patients receiving CSA.

Inclusion Criteria:

1. Age 2-40 years at onset of signs or symptoms of FSGS

2. Age </= 40 years at time of randomization (randomization date before 41th birthday)

3. Estimated GFR >/= 40 ml/min/1.73 m2 at most recent measure prior to randomization1

a) For patients < age 18 years: Schwartz formula

b) For patients >/= age 18 years: Cockroft-Gault formula

4. Up/c > 1.0 g protein/g creatinine on first am void at time of randomization1

5. Biopsy confirmed as primary FSGS (including all subtypes) by study pathologist. A minimum of 1 glomerulus demonstrating segmental sclerosison light microscopy will be required to confirm the diagnosis.

6. Steroid resistance: The patient must have demonstrated steroid resistance (defined as a failure to achieve a sustained Up/c < 1.0) based on at least one treatment course with high dose steroids prior to randomization that satisfies both of the following conditions:

a) a total treatment duration of at least 8 weeks

b) minimum cumulative dose of 56 mg/kg or 1680 mg of prednisone or its equivalent.

In addition, the patient must not have had a complete remission of proteinuria (Up/c < 0.2 or dipstick urine protein 0/ trace) subsequent to the latest qualifying 4week course demonstrating steroid resistance.

7. Willingness to follow the clinical trial protocol, including medications, and baseline and follow-up visits and procedures.

Patients may be taking ACEi, ARB, Vitamin E, or lipid lowering therapy.

Exclusion Criteria:

1. Secondary FSGS

2. Prior therapy with sirolimus, CSA, tacrolimus, MMF, or azathioprin (Imuran)

3. Treated with cytoxan, chlorambucil, levamisole, methotrexate, or nitrogen mustard in the last 30 days

4. Lactation, pregnancy, or refusal of birth control in women of child bearing potential1

5. Participation in another therapeutic trial concurrently or 30 days prior to randomization

6. Active/serious infection (including, but not limited to Hepatitis B or C, HIV)1

7. Malignancy

8. Blood pressure > 140/95 or > 95th percentile for age/height.

9. Patient is receiving 4 or more antihypertensive agents for the primary purpose of controlling blood pressure.

10. Patients with previously diagnosed diabetes mellitus Type I or II: the diagnosis of DM I or II will be based on local criteria for patients with an established diagnosis. If hyperglycemia is detected during the screening period, the WHO criteria for the diagnosis of DM I and II will be used.

11. Clinical evidence of cirrhosis or chronic active liver disease

12. Abnormal laboratory values at the time of study entry:

a. Absolute neutrophil count (ANC) < 2000/mm3, or

b. Hematocrit (HCT) < 28%

13. History of significant gastrointestinal disorder, e.g, severe chronic diarrhea (> 5 watery stools per day) or active peptic ulcer disease.

14. Organ transplantation

15. Obesity (based on estimated dry weight at onset of disease prior to steroid therapy) defined as

a. BMI > 97th percentile for age if age 2-20 years

b. BMI > 35 kg/m2 for age >=21 years

16. Allergy to study medications

17. Inability to consent/assent