The purpose of this study is to learn more about permeability factor-a protein found in some patients with a kidney disease called focal segmental glomerulosclerosis (FSGS). Patients with FSGS have proteinuria (excessive protein excretion in the urine) and glomerulosclerosis (scarring in the filtering part of their kidney called the glomerulus). The cause of FSGS is not known. It may be treated with various medicines, including steroids, cyclosporine and cyclophosphamide. Patients with high levels of permeability factor may be more likely to have a recurrence of FSGS after kidney transplant, damaging the transplanted kidney.

Patients 18 years of age and older with FSGS may be eligible for this study, including those 1) who have not been treated; 2) who require steroids to prevent a return of proteinuria; 3) whose proteinuria did not respond to steroid treatment; 4) who had a recurrence of FSGS after having a kidney transplant; and 5) who are on dialysis and are considering kidney transplantation.

All study participants will have 1 teaspoon of blood drawn to measure permeability factor and perform other tests related to FSGS. Additional samples may be requested if levels of the protein are very low or very high.

Patients who have recurrent FSGS following a kidney transplant may choose to 1) continue on their present immunosuppressive drugs; 2) try to treat the FSGS directly with plasma exchange; or 3) try to treat the FSGS directly with plasma exchange plus cyclophosphamide, an immune-suppressing medicine.

Plasma exchange is the removal of plasma (the fluid part of the blood) and replacement with a human albumin solution. This procedure may effectively remove the permeability factor from the plasma of patients with FSGS. Plasma exchange is done by a procedure called apheresis. In this procedure, whole blood is drawn through a needle in the forearm or by another method, the plasma is separated from the blood cells and removed, and the cells are returned to the patient through a second needle. Plasma exchange usually requires four to six apheresis procedures, each lasting about 2 hours.

Cyclophosphamide, which is approved to treat some leukemias, is also commonly used for FSGS. This drug might lower production of permeability factor, thereby reducing kidney damage. Patients with good kidney function will take standard doses of cyclophosphamide by mouth for 3 months. Patients with impaired kidney function will receive 75 percent of the ...

Focal segmental glomerulosclerosis (FSGS) is a renal syndrome characterized by proteinuria (usually nephrotic range), limited response to conventional therapy, and a poor renal prognosis, with progression to end stage renal failure in at least 50% of patients. As a syndrome, FSGS likely has many specific etiologies, only a few of which are well-defined. Recently, it has been suggested that some idiopathic FSGS patients have elevated circulating levels of a protein that induces glomerular permeability in vitro and in vivo. While there has been no consistent term for this factor, it will be termed here FSGS permeability factor (FPF).

The purposes of the present study are five fold:

1. To identify a population of FSGS patients with elevated FPF levels
2. To examine RNA expression profiles of peripheral blood mononuclear cells (PBMC) in FSGS patients with elevated FPF levels
3. To define the kinetics of FPF disappearance and reappearance in FSGS patients receiving Immunomodulatory therapy and in the case of patients with recurrent FSGS following renal transplant, those receiving plasma exchange
4. To identify immunosuppressive agents which are successful in inducing sustained reduction in FPF levels
5. To determine in patients with FSGS who are awaiting renal transplant, whether sustained reduction in FPF levels is associated with reduced risk of recurrent FSGS.

Patient participation is divided into an evaluation phase, in which FPF levels, RNA expression profiles, and patient eligibility for participation in treatment protocols are determined, and a treatment phase in which specific immunomodulatory therapy is introduced in an open label fashion. We propose to define carefully the relationship between elevated FPF and remission of proteinuria in patients with FSGS in native kidneys, following treatment with standard therapies (daily prednisone, cyclophosphamide) and experimental therapies (pulse dexamethasone, pirfenidone). In patients with recurrent FSGS in renal allografts, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide. In patients with elevated FPF levels who are awaiting renal transplantation, we will determine the kinetics of FPF following plasma exchange and following plasma exchange plus cyclophosphamide, and examine the rate of recurrent FSGS in these patients.

• Procedure: Plasma exchange
• Drug: Cyclophosphamide

• Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol. 1998 Jul;9(7):1333-40. Review. No abstract available.
• Cameron JS. Recurrent renal disease after renal transplantation. Curr Opin Nephrol Hypertens. 1994 Nov;3(6):602-7. Review.
• Valeri A, Barisoni L, Appel GB, Seigle R, D'Agati V. Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study. Kidney Int. 1996 Nov;50(5):1734-46.

• INCLUSION CRITERIA:

  1. Patients with idiopathic focal segmental glomerulosclerosis on renal biopsy, including the following categories:

     A) Untreated FSGS

     B) Steroid-dependent FSGS

     C) Steroid resistant FSGS

     D) Recurrent FSGS, with functioning allograft

     E) FSGS in ESRD, receiving hemodialysis

  2. Adults greater than or equal to18 will be eligible for all studies.
  3. Children greater than 20 kilograms, will be eligible for all branches of the study except for treatment of steroid resistant FSGS with pirfenidone, as pirfenidone has not previously been administered to pediatric patients in any setting. Children less than 20 kilograms will be excluded from the study for the following reason: plasma exchange in patients less than 20 kilograms requires a red blood cell transfusion, which significantly increases the risk of the procedure by exposing the patient to the risk of transfusion associated infections, and the safety of an aggressive course of plasma exchange has not been established in this population.

EXCLUSION CRITERIA:

1. Secondary FSGS: HIV-associated FSGS or hyperfiltration FSGS, including FSGS associated with congenital renal abnormalities, renal mass reduction, reflux nephropathy, interstitial nephritis, and sickle cell anemia are excluded.
2. Patients with disease associated with immunosuppression, other than chronic renal failure.
3. The presence of malignancy or the history of other serious, complicating illness such as myocardial infarction or cerebrovascular accident in the past six months, at the discretion of the investigators.
4. For plasma exchange: A Department of Transfusion Medicine consultant will evaluate all potential plasma exchange patients. Those with prolonged PT, PTT, platelet count less than 100,000 or receiving anticoagulant therapy will undergo plasma exchange only if the consultant considers this to be safe.
5. For prednisone: uncontrolled diabetes mellitus (requiring greater than 100 units of insulin/day with the concurrence of the Endocrinology consultant), active infection including hepatitis B or C (if that is the advice of the Hepatology consultant), infection with HIV (as these patients are at increased risk of avascular necrosis), other active infection (if that is the advice of the Infectious Disease consultant), history of avascular necrosis or bone densitometry indicating bone mass less than 2SD below normal, active ulcer disease, history of steroid-induced psychosis, morbid obesity, positive PPD or history of past positive PPD without adequate treatment are excluded.
6. For Cyclophosphamide:

A) Allergy or hypersensitivity to cyclophosphamide

B) Leukocyte less than 3000 cells/microliter or ANC less than 1500 cells/microliter or evidence of bone marrow compromise

C) Prior irradiation to the heart or therapy with doxorubicin or other cardiotoxic medication (may increase the risk for cardiotoxicity)

D) Peritoneal dialysis, as there is no published evidence that cyclophosphamide metabolites can be safely removed.

E) Certain drugs will be used with caution or avoided. Barbiturates and phenytoin induce the hepatic enzymes that metabolize cyclophosphamide and therefore if these medications are required, cyclophosphamide doses may need to be increased to achieve a comparable immunosuppressive effect. Drugs that inhibit cyclophosphamide metabolism include allopurinol, imipramine, and phenothiazines, chloramphenicol and chlorpromazine; these drugs will be avoided. NSAID increase the risk of hyponatremia; these drugs will be avoided.