Clinical trial NCT00007475: Permeability Factor in Focal Segmental Glomerulosclerosis
Official title: Permeability Factor in Focal Segmental Glomerulosclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Focal Segmental Glomerulosclerosis
Keywords: Plasma Exchange
Cyclophosphamide
Proteinuria
Hemodialysis
Expression Profiling
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2000-12-25
Enrollment: 15
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: * 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.

Primary outcomes:
measure: Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide.
timeFrame: every 3 months up to a year followed with native kidneys
Secondary outcomes:
measure: Comparison of RNA Expression Profiles in PBMC From Patients With FPF, Without FPF and Control Subjects
timeFrame: End of study
measure: Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange.
timeFrame: End of study
measure: Correlate the Effect of Immunosuppressive Agents Which Reduce Proteinuria in Recurrent FSGS With the Effect on FPF Levels
timeFrame: End of study
measure: Determine Whether Renal Transplantation in Patients Whose Elevated FPF Levels Have Been Reduced for a Sustained Period is Associated With a Reduced Prevalence of Recurrent FSGS.
timeFrame: End of study
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Jeffrey B Kopp, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol. 1998 Jul;9(7):1333-40. doi: 10.1681/ASN.V971333. No abstract available.
citation: Cameron JS. Recurrent renal disease after renal transplantation. Curr Opin Nephrol Hypertens. 1994 Nov;3(6):602-7. doi: 10.1097/00041552-199411000-00007.
citation: 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. doi: 10.1038/ki.1996.493.