Permeability Factor in Focal Segmental Glomerulosclerosis
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.
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.
-  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.