Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
Condition: Fibrosis; Focal Glomerulosclerosis; Kidney Failure; Nephrotic Syndrome; Proteinuria
MeSH terms: Renal Insufficiency; Proteinuria; Nephrotic Syndrome; Nephrosis; Glomerulosclerosis, Focal Segmental; Fibrosis
Intervention: Pirfenidone
Intervention description: During the study drug period of 12 months, patients will receive oral pirfenidone daily. For patients whose initial renal function is 50-80 ml/min as assessed by the MDRD equation, the initial pirfenidone dosage will be calculated at 40 mg/kg/d, with a maximum dose of 800 mg TID. For patients whose initial renal function is 30-50 ml/min, the initial dose will be 30 mg/kg/d. For patients whose initial renal function is between 15 and 30 ml/min, the initial dose will be 20 mg/kg/d.
Intervention MeSH terms: Pirfenidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Fibrosis; Nephrotic Syndrome; Proteinuria; Renal Failure; TGF-Beta; Focal Segmental Glomerulosclerosis; FSGS

Summary:

      This study will examine the effectiveness of the drug pirfenidone in treating focal segmental
      glomerulosclerosis (FSGS). Patients with this disease have kidney fibrosis (scarring) and
      proteinuria (excessive excretion of protein in the urine). About half of patients with FSGS
      eventually require kidney dialysis or transplant. Steroids, which are currently used to treat
      the disease, are effective in only a minority of patients. Other drugs, such as cyclosporin
      and cyclophosphamide, improve proteinuria in a very small percentage of patients and have
      serious side effects.

      Patients with FSGS who wish to participate in this study will undergo pre-study evaluation
      with blood and urine tests. Patients must be on a stable dose of an ACE inhibitor (a drug
      that lowers blood pressure and reduces proteinuria) for at list 6 months before starting
      pirfenidone therapy. (Patients who are not already taking an ACE inhibitor will be started on
      the drug; those who cannot tolerate ACE inhibitors will be given a different drug.) Patients
      with elevated cholesterol will take a cholesterol-lowering drug. A diet containing
      approximately 1 gram of protein per kilogram of body weight per day will be recommended.

      Patients will take pirfenidone by mouth 3 times a day for 12 months. Blood and urine will be
      tested once a month, either at NIH or by the patient's local kidney specialist. They will
      collect two 24-hour urine samples at the beginning of the treatment period, at 2-month
      intervals throughout the study, and at a 6-month follow-up. Patients will also be asked to
      give three to five tubes of blood and urine samples for analysis during the study.

      In animal studies, pirfenidone improved kidney function and proteinuria and reduced kidney
      scarring in rats with a disease similar to FSGS. In human studies, pirfenidone improved
      breathing and survival in patients with lung fibrosis.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

               1. Adults greater than or equal to 18 years of age.

               2. Patients will provide informed consent.

               3. Biopsy proven FSGS.

               4. Glomerular filtration rate of at least 25 and no more than 80 ml/minute as
                  assessed by the 4 variable Modification of diet in renal disease GFR equation.

               5. At least 6 months of renal function data must be available prior to the patient's
                  receiving pirfenidone, and renal function must show a rate of decline of greater
                  than or equal to 0.4 ml/min/month during this baseline period.

               6. Patients must have received no glucocorticoids, cyclophosphamide, mycophenolate
                  or other immunosuppressive drugs for at least 2 months prior to the study period.

               7. Patients must have received no cyclosporin for at least 6 months prior to the
                  study period.

               8. Patients must have been taking an angiotensin converting enzyme inhibitor (ACEI)
                  or angiotensin receptor blocker (ARB) at a stable dose for at least 6 months,
                  unless intolerant of both classes of medication.

               9. Patients who are HIV seropositive will receive standard care for HIV disease
                  (patients receiving immune-modulating therapy will be excluded).

              10. Women with child-bearing potential must maintain an effective birth control
                  regimen (oral contraceptive, intrauterine device, barrier plus spermicide).

              11. Men will be advised that although Ames testing has been negative for any evidence
                  of mutagenicity, they should consider use of contraceptives during the study
                  period as well.

        EXCLUSION CRITERIA:

          1. Inability to give informed consent or cooperate with study.

          2. Known intolerance to pirfenidone.

          3. Evidence of FSGS associated with an additional primary or secondary glomerular disease
             (e.g. diabetes, membranous nephropathy, IgA nephropathy).

          4. Recent (within 6 months) history of myocardial infarction.

          5. History of peptic ulcer within 6 months.

          6. History of cerebrovascular disease manifested by transient ischemic attack or
             cerebrovascular accident within 6 months.

          7. Pregnancy, breast feeding or inadequate birth control.

          8. History of photosensitivity dermatitis.

          9. Concurrent drug treatment with gemfibrozil, cyclosporin or erythromycin,
             potassium-sparing diuretics and other drugs which may potentiate hyperkalemia, or
             concurrent immunosuppresive medications.

         10. Requirement for NSAID therapy.

         11. Requirement for interleukin-2 therapy or other immune-modulating medication.

         12. Existence of any other condition which would complicate the implementation or
             interpretation of the study.

         13. Renal transplant.

         14. Evidence of significant hepatic disease, as indicated by serum transaminases greater
             than 3 times upper limit of normal, protime greater than 2 seconds prolonged.