Focal segmental glomerulosclerosis (FSGS) and minimal change disease are kidney diseases
that are associated with increased excretion of protein in the urine. Approximately half of
FSGS patients will lose kidney function within 8 years of diagnosis and will require
dialysis. The purpose of this study is to determine whether intermittent oral steroid
therapy can cause sustained remission of FSGS and MCD.
Approximately 70 participants, including adults and children older than age 2, will be
enrolled in this study. They will receive 48 doses of oral dexamethasone over a period of
48 weeks. One group will take two daily doses every 2 weeks; the other group will take four
daily doses every 4 weeks. Doctors will monitor participants before, during, and after the
steroid treatment with extensive exams and testing. At the completion of the study,
researchers will evaluate the safety and efficacy of the drug treatment.
The major causes of primary nephritic syndrome in adults and children are idiopathic
podocyte diseases, minimal change (MCD) and focal segmental glomerulosclerosis (FSGS). Our
objective is to determine whether intermittent oral dexamethasone administered over 48 weeks
can induce complete remission in these patients. This is an open-label multi-center pilot
study designed to obtain preliminary evidence of efficacy and to establish safety. This is
part of a long-term effort to define the most effective mode of administering pulse
dexamethasone and is expected to lead to a trial comparing daily prednisone to pulse
We will enroll up to 70 patients with nephritic-level proteinuria due to biopsy-proven MCD
(up to 30 patients) or FSGS (up to 40 patients). We will include adults and children
greater than 2.0 years of age. Children with MCD must have received a minimum of 4 weeks
and a maximum of 10 weeks of high-dose daily steroids, since many children are responsive to
short courses of daily steroids; these requirements will define a steroid-resistant
population. For children with FSGS and adults with MCD or FSGS, there is no minimum
duration of prior steroids and there is a maximum of 8 weeks of prior high-dose daily
steroids; these requirements will define a population that has received a short steroid
course without response. If steroids have been used, inclusion criteria require persistent
nephrotic syndrome (thus excluding steroid-sensitive nephrotic syndrome, whether
steroid-dependent or frequently relapsing).
Patients may enroll at NIH or at collaborating centers. Those patients who enroll at NIH
will visit the NIH Clinical Center at least 4 times. Patients enrolled at collaborating
centers have the option to come to the NIH Clinical Center to complete research tests; under
these circumstances they will be enrolled as NIH research subjects.
Patients will receive 48 doses of oral dexamethasone over a period of 48 weeks. Patients
will be randomized to one of two arms: 2 daily doses every 2 weeks or 4 daily doses every 4
weeks. The rationale is to test whether increased frequency dosing has greater efficacy
with acceptable safety. For adult patients, we have a record of safety with pulse
dexamethasone from the FSGS Dexamethasone study as well as from published studies for other
diseases. Therefore, for adults each pulse will be 50 mg/m(2) during the first 12 weeks and
each pulse will be 25 mg/m(2) during the next 36 weeks. The trial for pediatric patients
involves dose escalation, as there is little experience with pulse dexamethasone for
podocyte diseases in this age group. In pediatric stage 1, each dexamethasone pulse will be
25 mg/m(2) over 48 weeks. When 4 patients in each arm have completed 48 weeks of therapy,
safety and efficacy will be evaluated. If the evaluation is positive, we will embark on
pediatric stage 2, in which dexamethasone pulses will be 50 mg/m(2) during the first 12
weeks and 25 mg/m(2) during the next 36 weeks (the same as the adult regimen).
The primary endpoint will be the presence of complete remission 48 weeks after beginning
therapy. Secondary endpoints will include complete and partial remission at 48 weeks, and
complete and partial remission at 104 weeks. Assessment of remission will be by 24 hour
urine collection in adults and children greater than 13.0 years and first void urine samples
in children less than 13.0 years. Patients will be evaluated for manifestations of steroid
toxicity, including growth rate (children), ophthalmologic complications, adrenal
suppression, osteoporosis, a vascular necrosis, and psychological disturbances.
- INCLUSION CRITERIA:
1. Adults and children greater than 2.0 years of age are eligible. We will exclude
children less than 2.0 years of age in light of the higher risk of steroid
therapy in this age group and the higher likelihood genetic or syndromic FSGS,
which is less likely to respond to steroids.
A) Biopsy-proven MCD and its variants, including IgM nephropathy and MCD with
B) Biopsy-proven FSGS, including idiopathic FSGS and collapsing FSGS. We will
exclude patients with HIV-associated FSGS, as the risks of steroids are
increased in these patients. We will exclude hyperfiltration FSGS associated
with morbid obesity (BMI greater than 40 kg/m(2)), sickle cell anemia, reflux
nephropathy, chronic tubular injury, congenital renal anomalies, and reduced
nephron mass; the rationale is that these FSGS variants are considered
refractory to steroids.
3. Proteinuria: patients must have nephrotic range proteinuria. Baseline tests will
be obtained when patients have been off all immunosuppressive therapy for
greater than or equal to 1 month.
4. Renal function: estimated GFR must be greater than or equal to 40
ml/min/1.73m(2) at the time of study entry; In children weighing less than 40kg,
GFR will be estimated by the Schwartz formula and expressed as GFR/1.73m(2): GFR
equal to [0.7 (males) or 0.57 (females) X height (cm)]/ serum creatinine.
5. Angiotensin antagonists: Patients must be receiving angiotensin antagonist
therapy, at any dose approved by the FDA. Nephrotic range proteinuria will be
defined as urine protein greater than or equal to 3.5 g/1.73m(2)/d (adults) and
greater than 50 mg/kg (children less than 40 kg) while receiving maximally
tolerated dose of angiotensin antagonist therapy for at least 4 weeks prior to
6. Prior immunosuppressive therapy:
For children with MCD, we require a minimum of 4 weeks and a maximum of 10 weeks
of daily steroid therapy at a dose of greater than or equal to 60 mg/m(2) with
proteinuria persisting in the nephrotic range (excluding steroid-sensitive,
steroid-dependent and frequently relapsing MDC).
For children with FSGS and adults with MCD and FSGS, we require no minimum and a
maximum of 8 weeks of daily or alternate day steroids at a dose of greater than
0.5 mg/kg with proteinuria persisting in the nephrotic range.
Patients with prior immunosuppressive therapy other than steroids are eligible.
7. If hypertensive, adequate blood pressure control (target BP less than 125/75 mm
Hg at greater than 75% of measurements in adults).
8. Women with reproductive potential who are sexually active must maintain an
effective birth control regimen (oral contraceptive, intrauterine device, or
barrier method plus spermacide) and must have a negative urine HCG test prior to
9. Patients must either have a negative PPD test within 3 months of study entry
while off immunosuppressive therapy or, if they have a history of positive PPD,
they must have appropriate evaluation to exclude untreated tuberculosis (with
the advice of an Infectious Disease consultant).
1. Patients with diabetes mellitus type 1 will be excluded, as these patients typically
have brittle diabetic control that increases the risk of steroid treatment. Patients
with diabetes mellitus type 2 will be included they manifest good glycemic control
(glycoyslated hemoglobin less than 7.5%), if they have lack proliferative retinopathy
(the presence of proliferative retinopathy would place them at high risk for vision
loss if steroids worsened glycemic control) and if they have had a renal biopsy
within 6 months of study entry that shows no evidence for diabetic nephropathy.
2. Poorly controlled hypertension (greater than 25% of values greater than 125/75).
3. Evidence of significant chronic or occult infection. Specifically, subjects must not
have evidence of active hepatitis B or hepatitis C infection, or HIV-1 infection, or
untreated mycobacterial infection. Minor infections, such as skin or nail fungal
infections or other infections with the advice of an Infectious Disease consultant,
will not be the basis for exclusion.
4. Immunosuppressive medication other than glucocorticoids, whether for podocyte disease
or another indication, must have been discontinued greater than 8 weeks prior to
study entry. This does not apply to topical immunosuppressant medication.
6. Existence of any other condition that would complicate the implementation or
interpretation of the study.