Permeability Factor in Focal Segmental Glomerulosclerosis

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.

Study Overview

• Status: Completed
• Conditions: Focal Segmental Glomerulosclerosis
• Intervention / Treatment: Procedure: Plasma exchange; Drug: Cyclophosphamide

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Plasma Exchange + 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.

Procedure: Plasma exchange; A course of plasma exchange of 5 treatments over 10 days, then administration of cyclophosphamide.; Other Names: Plasmapheresis; 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.; Other Names: Cytophosphane

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in Proteinuria in Recurrent FSGS Following Renal Transplant With Plasma Exchange and Cyclophosphamide.	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.	every 3 months up to a year followed with native kidneys

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of RNA Expression Profiles in PBMC From Patients With FPF, Without FPF and Control Subjects	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: 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.; 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.	End of study
Define the Kinetics of FPF in FSGS Patients Receiving Immunomodulatory Therapy or Plasma Exchange.	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: Terry Phillips at NIH developed an assay that looked promising prior to his retirement.; Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.	End of study
Correlate the Effect of Immunosuppressive Agents Which Reduce Proteinuria in Recurrent FSGS With the Effect on FPF Levels	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: Terry Phillips at NIH developed an assay that looked promising prior to his retirement.; Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.	End of study
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.	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: Terry Phillips at NIH developed an assay that looked promising prior to his retirement.; Avi Rosenberg, NCI has developed promising ELISA-style assay, and mass spectrometry assay, being refined.	End of study

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Korbet SM. Primary focal segmental glomerulosclerosis. J Am Soc Nephrol. 1998 Jul;9(7):1333-40. doi: 10.1681/ASN.V971333. No abstract available.
• Cameron JS. Recurrent renal disease after renal transplantation. Curr Opin Nephrol Hypertens. 1994 Nov;3(6):602-7. doi: 10.1097/00041552-199411000-00007.
• 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.

Study record dates

Study Major Dates

• Study Start: December 1, 2000
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: December 22, 2000
• First Submitted That Met QC Criteria: December 22, 2000
• First Posted (Estimate): December 25, 2000

Study Record Updates

• Last Update Posted (Estimate): February 10, 2016
• Last Update Submitted That Met QC Criteria: February 8, 2016
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Cyclophosphamide; Proteinuria; Hemodialysis; Plasma Exchange; Expression Profiling
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Nephritis; Glomerulonephritis; Glomerulosclerosis, Focal Segmental; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: 010053; 01-DK-0053 (Other Identifier: National Institutes of Health)