Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)

Pirfenidone in Focal Segmental Glomerulosclerosis:Phase II Study

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.

The objective of this pilot phase II trial is to evaluate the ability of pirfenidone, a novel anti-fibrotic agent, to reduce the proteinuria and slow the rate of progression of renal insufficiency in patients with focal segmental glomerulosclerosis (FSGS). We will enroll 25 patients with renal biopsy proven FSGS and evidence of impaired renal function (glomerular filtration rate, GFR, of 10-80 ml/min; after 1/02 must have GFR greater than 25 ml/min) as assessed by the 4 variable Modification of Diet in Renal Disease equation. As standard of care therapy, all patients will also receive angiotensin converting enzyme inhibitor (ACEI) therapy, and will receive an HMG Co-A reductase inhibitor drug if hypercholesterolemic. Preliminary evaluation will assure that the patients meet the study requirements, and an evaluation period will be used to ensure that patients are on maximal conservative therapy prior to the baseline period. Patients will receive treatment with pirfenidone daily, with dose adjusted for body weight and level of kidney function. The primary end point will be the decrease glomerular filtration as a marker of glomerular injury; reduction in proteinuria will be a secondary end-point. If the pilot study suggests this drug delays progression of renal insufficiency or reduces proteinuria in patients with FSGS, we will proceed with a large scale randomized, placebo-controlled study.

• 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.