Inclusion Criteria:

• Age 2-40 years at onset of signs or symptoms of FSGS
• Age ≤ 40 years at time of randomization (randomization date before 41st birthday)

• Estimated GFR ≥ 40 ml/min/1.73 m2 at most recent measure prior to randomization

  • For participants < age 18 years: Schwartz formula
  • For participants ≥ age 18 years: Cockroft-Gault formula
• Up/c > 1.0 g protein/g creatinine on first am void at time of randomization
• Biopsy confirmed as primary FSGS (including all subtypes) by study pathologist. A minimum of 1 glomerulus demonstrating segmental sclerosis on light microscopy will be required to confirm the diagnosis.

• Steroid resistance: The participant 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 which satisfies both of the following conditions:

  • minimal treatment duration of 4 weeks
  • minimum cumulative dose of 56 mg/kg or 1680 mg of prednisone or its equivalent. In addition, the participant must not have had a complete remission of proteinuria (Up/c < 0.2 or dipstick urine protein 0/trace) subsequent to the latest qualifying 4-week course demonstrating steroid resistance.
• Willingness to follow the clinical trial protocol, including medications, and baseline and follow-up visits and procedures.
• Participants may be taking ACEI, ARB, Vitamin E, or lipid lowering therapy.

Exclusion Criteria:

• Secondary FSGS
• Prior therapy with sirolimus, CSA, tacrolimus, MMF, or azathioprin (Imuran)
• Treated with cytoxan, chlorambucil, levamisole, methotrexate, or nitrogen mustard in the last 30 days
• Lactation, pregnancy, or refusal of birth control in women of child bearing potential
• Participation in another therapeutic trial concurrently or 30 days prior to randomization
• Active/serious infection (including, but not limited to Hepatitis B, C, or HIV)
• Malignancy
• Blood pressure > 140/95 or > 95th percentile for age/height.
• Participant is receiving 4 or more antihypertensive agents for the primary purpose of controlling blood pressure.
• Participants with previously diagnosed diabetes mellitus type I or II: the diagnosis of DM I or II will be based on local criteria for participants 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.
• Clinical evidence of cirrhosis or chronic active liver disease

• Abnormal laboratory values at the time of study entry:

  • Absolute neutrophil count (ANC) < 2000/mm3, or
  • Hematocrit (HCT) < 28%
• History of significant gastrointestinal disorder, e.g, severe chronic diarrhea (> 5 watery stools per day) or active peptic ulcer disease.
• Organ transplantation

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

  • BMI > 97th percentile for age if aged 2-20 years
  • BMI > 40 kg/m2 for age ≥21 years
• Allergy to study medications
• Inability to consent/assent

Note: Participants with conditions meeting exclusion criteria at a particular evaluation for eligibility may be re-evaluated at a later time to determine if the conditions have changed so that all entry criteria are met. In particular, if blood pressure > 140/95 or > 95th percentile for age/height while the participant is on less than three antihypertensive agents, the participant may be re-evaluated for eligibility after adding other antihypertensive agents so long as the total number of agents does not exceed three.