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.

- 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.