Protocol Number: 01-DK-0053

Title:

Permeability Factor in Focal Segmental Glomerulosclerosis

Number:

01-DK-0053

Summary:

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 standard dose for 3 months.

Patients with kidney failure who have elevated levels of permeability factor and are considering a kidney transplant will undergo plasma exchange. If their permeability factor levels rise again, they will have a second course of plasma exchange plus cyclophosphamide.

All patients with elevated permeability factor who undergo treatment for FSGS may be asked to give 1 teaspoon of blood every month or every 3 months while undergoing treatment and then every 3 months for a year after therapy ends to see what treatments successfully reduce protein levels.

Sponsoring Institute:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

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

Adults greater than or equal to18 will be eligible for all studies.

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:

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.

Patients with disease associated with immunosuppression, other than chronic renal failure.

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.

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.

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.

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.

Special Instructions: Currently Not Provided

Keywords:

Plasma Exchange

Cyclophosphamide

Proteinuria

Hemodialysis

Expression Profiling

Recruitment Keywords:

None

Conditions:

Focal Glomerulosclerosis

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Idiopathic collapsing focal segmental glomerulosclerosis: a clinicopathologic study

Primary focal segmental glomerulosclerosis

Recurrent renal disease after renal transplanation

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