Permeability Factor in Focal Segmental Glomerulosclerosis

Phase 1

Completed

Conditions: Focal Segmental Glomerulosclerosis

Interventions: Procedure: Plasma exchange
Drug: Cyclophosphamide

Registration Number: NCT00007475

Lead Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Plasma Exchange + Cyclophosphamide	Plasma exchange	Procedure/Surgery: Plasma exchange A course of plasma exchange of 5 treatments over 10 days, then administration of cyclophosphamide. Drug: Cyclophosphamide For GFR \> 50 ml/min/1.73 m2 received oral cyclophosphamide at a dose of 2 mg/kg/ day for 3 months. For GFR \< 50 ml/min/1.73 m2 but \> 10 ml/min/1.73 m2 will receive oral cyclophosphamide at a 25% reduced dose or 1.5 mg/kg/d for 3 months.
Plasma Exchange + Cyclophosphamide	Cyclophosphamide	Procedure/Surgery: Plasma exchange A course of plasma exchange of 5 treatments over 10 days, then administration of cyclophosphamide. Drug: Cyclophosphamide For GFR \> 50 ml/min/1.73 m2 received oral cyclophosphamide at a dose of 2 mg/kg/ day for 3 months. For GFR \< 50 ml/min/1.73 m2 but \> 10 ml/min/1.73 m2 will receive oral cyclophosphamide at a 25% reduced dose or 1.5 mg/kg/d for 3 months.

Primary Outcome Measures

Name	Time	Method
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide.	every 3 months up to a year followed with native kidneys	Outcomes for FSGS occurring in native kidneys: A. Complete remission: proteinuria \<0.3 g/d ; B. Partial remission: proteinuria between 0.3 and 2 g/d ; C. Incomplete response: proteinuria between 2 and 3.5 g/d ; D. Relapse: return to proteinuria ≥3.5 g/d ; Note that counts within each category A-D may be summarized relative to remaining categories, as a proportion (relative to complement of the whole group count) with calculations implicitly based on zero/one valued binary variables, whose means are proportions, so to report 95% confidence intervals calculated using an exact binomial distribution.

Secondary Outcome Measures

Name	Time	Method
Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange.	End of study	Provisional assay of a molecular identification of FPF (current candidate: cardiotrophin-like cytokine 1) using an isolation approach based on sequential precipitation results in a 100-fold purification. Note: Focal segmental glomerulosclerosis Permeability Factor (FPF) assay had not yet been developed to an extent that it could be applied to all enrollees in the current trial; provisional values were assayed for 3 of the first 4 enrollees using a version implemented by Dr. Virginia Savin, whose lab is actively investigating the above isolation approach, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF, mentioned here for interested readers of this trial report, include: 1. Terry Phillips at NIH developed an assay that looked promising prior to his retirement. 2. Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.
Comparison of RNA Expression Profiles in PBMC From Patients With FPF, Without FPF and Control Subjects	End of study	No RNA expression profiles have been obtained as FSGS Permeability Factor (FPF) levels NOT available -- its assay has not yet been developed to an extent that it could be applied to all enrollees of this current trial. Note that provisional values (targeting current candidate molecule: cardiotrophin-like cytokine 1) were assayed for 3 of the first 4 enrollees using assay by Dr. Virginia Savin, whose lab is actively investigating a molecular identification of FPF using an isolation approach based on sequential precipitation results in a 100-fold purification, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF include: 1. Terry Phillips at NIH developed an assay that looked promising but after his retirement it has not been possible for other researchers to get this working. 2. Avi Rosenberg, NCI has developed a promising ELISA-style assay, as well as some work in a mass spectrometry assay, and this is being further refined.
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.	End of study	Provisional assay of a molecular identification of FPF (current candidate: cardiotrophin-like cytokine 1) using an isolation approach based on sequential precipitation results in a 100-fold purification. Note: Focal segmental glomerulosclerosis Permeability Factor (FPF) assay had not yet been developed to an extent that it could be applied to all enrollees in the current trial; provisional values were assayed for 3 of the first 4 enrollees using a version implemented by Dr. Virginia Savin, whose lab is actively investigating the above isolation approach, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF, mentioned here for interested readers of this trial report, include: 1. Terry Phillips at NIH developed an assay that looked promising prior to his retirement. 2. Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.
Correlate the Effect of Immunosuppressive Agents Which Reduce Proteinuria in Recurrent FSGS With the Effect on FPF Levels	End of study	Provisional assay of a molecular identification of FPF (current candidate: cardiotrophin-like cytokine 1) using an isolation approach based on sequential precipitation results in a 100-fold purification. Note: Focal segmental glomerulosclerosis Permeability Factor (FPF) assay had not yet been developed to an extent that it could be applied to all enrollees in the current trial; provisional values were assayed for 3 of the first 4 enrollees using a version implemented by Dr. Virginia Savin, whose lab is actively investigating the above isolation approach, but the fraction remains a complex mixture on SDS-PAGE (Sharma 1999). Other investigators of FPF, mentioned here for interested readers of this trial report, include: 1. Terry Phillips at NIH developed an assay that looked promising prior to his retirement. 2. Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.