This study will evaluate the safety and effectiveness of a new immunosuppressive drug,
sirolimus, in reducing the amount of protein in the urine in patients with membranous
nephropathy. This condition involves damage to the walls of tiny blood vessel filters in the
kidneys called glomeruli, which allows blood proteins to leak into the urine. Patients have
low blood protein levels and high blood cholesterol. Some patients may have leg swelling,
impaired kidney function, blood vessel and heart disease, and a risk of emboli (blood clots
that travel to the lungs). Drugs currently used to treat membranous nephropathy vary in their
effectiveness among patients and can cause severe side effects.
The Food and Drug Administration has approved sirolimus for suppressing the immune system of
patients who have had a kidney transplant to reduce the risk of organ rejection. The drug
does not have certain side effects that have caused problems for patients treated with other
immunosuppressants, such as: prednisone (weight gain, round face, diabetes, weak and
fractured bones, and cataracts); cyclophosphamide (fertility problems, bladder injury and
bladder cancer, and other cancers); chlorambucil (fertility problems, seizures, acute
leukemia, and other cancers); and cyclosporine (kidney toxicity, increased facial hair, and
Patients 13 years of age or older with idiopathic membranous nephropathy or lupus membranous
nephropathy may be eligible for this study. Candidates must have completed at least one month
of treatment with a stable dose of angiotensin converting enzyme (ACE) inhibitors or
angiotensin receptor blockers (ARBs). They will be screened with a medical history, physical
examination, blood tests, skin test for exposure to tuberculosis, and an examination for
infection, cancers, and other conditions that can cause membranous nephropathy.
Participants will take sirolimus once a day for 1 year, except for the first day of
treatment, when they will take three doses to quickly bring their blood levels of the drug up
to a therapeutic level. They will undergo evaluations at the NIH in Bethesda, Maryland, at
baseline (before starting treatment) and again at 1- to 4-month intervals during the study.
In addition, they will have blood tests every week for the first month and every 2 weeks for
the second month; then blood and urine tests once a month for the next 10 months of treatment
and then every 4 months for a 12-month period after treatment stops. These tests will
evaluate drug side effects and the response to therapy, and will determine if the therapeutic
benefits persist long-term when treatment stops.
Patients will also be asked to have optional kidney function tests during the baseline
evaluation and at the end of the follow-up period to measure kidney filtration and blood flow
rates. Those who participate will be given fluids and other substances by vein to accurately
measure kidney function. They will then have blood and urine samples collected about four
times over a 1-hour period after drinking fluids to increase urine output.
Patients who experience a substantial increase in proteinuria or substantial decrease in
kidney function during the course of treatment will stop taking sirolimus and be taken off
This is a phase 2 trial to evaluate the safety and effectiveness of a new immunosuppressive
drug, sirolimus, in patients with idiopathic and lupus membranous nephropathy. Patients (age
greater than or equal to 13 years) will be invited to participate if they have persistent
nephrotic range proteinuria despite standard treatment with an angiotensin converting enzyme
inhibitor or an angiotensin receptor blocker for at least one month, unless intolerant. These
individuals are at risk for renal function deterioration as well as cardiovascular and
thrombo-embolic complications of the nephrotic syndrome. Renal function, the degree of
proteinuria and side effects will be monitored closely throughout the study. Physiologic
measures of glomerular function will be examined at study entry and at the conclusion of the
- INCLUSION CRITERIA:
Ability and willingness to provide informed consent (adults greater than or equal to 18
years) or assent (children greater than or equal to 13 years) to all aspects of the study
after full information is provided.
Nephrotic range proteinuria that persists for at least 3 months.
Nephrotic range proteinuria that persists despite angiotensin antagonist therapy (ACE
inhibitor or ARB) for at least on month, unless intolerant. If patients have not started
ACE inhibitor therapy before they are referred to NIH, we plan to start lisinopril 5 mg
daily. We will advance the dose of ACE inhibitor as tolerated. Nephrotic range proteinuria,
defined as 24 hour urine protein excretion greater than or equal to 3.5 g/d, must be
documented in at least two 24 hour urine collections obtained during the month prior to
initiating sirolimus. Incomplete urine collections (based on inadequate creatinine
excretion) will be excluded.
Renal biopsy must reveal typical changes of membranous nephropathy by light and electron
SLE as defined by the presence of at least 4 criteria established by the American
Rheumatism Association (Lupus Membranous Nephropathy) or no evidence of a secondary form of
membranous nephropathy (Idiopathic Membranous Nephropathy).
Intolerance to sirolimus or prior use of sirolimus for membranous nephropathy.
Estimated GFR less than 30 mL/min/1.73(2) (determined by the 5 variable version of the MDRD
Study prediction equation).
Immunosuppressive medications or experimental medications of any type during the two-month
period prior to initiating sirolimus, with the following two exceptions:
First, patients with lupus membranous nephropathy are permitted to have received modest
doses of corticosteroids (no more than the equivalent of prednisone 10mg/day) for control
of extra-renal manifestations of SLE during the two-month period prior to starting
Second, patients with worsening nephrotic syndrome (urine protein excretion rate doubles
+/or serum albumin decreases by greater than or equal to 1.0 g/ dL to less than 2.5 g/dL on
at least 2 determinations during or following a previous immunosuppressive treatment)
should fulfill the following criteria:
a) should be off prednisone for at least 2 weeks before performing the baseline evaluation
and starting sirolimus (if the patient has idiopathic membranous nephropathy): b) should be
on low-dose corticosteroids (no more than the equivalent of prednisone 10 mg/day) for at
least 2 weeks before performing the baseline evaluation and starting sirolimus (if the
patient lupus membranous nephropathy); c) should be off cyclosporine for at least 2 weeks
before performing the baseline evaluation and starting sirolimus; d) should be off
cyclophosphamide, chlorambucil, azathioprine and mycophenolate mofetil for at least 4 weeks
before performing the baseline evaluation and starting sirolimus;
Children less than 13.0 years.
Active acute or chronic infection requiring antimicrobial therapy or serious viral
infection (e.g. HIV, hepatitis, herpes zoster). Patients with a reactive PPD must have
completed a 6 to 12 month course of isoniazid as recommended by an infectious disease
consultant. Patients with a non-reactive PPD and non-reactive anergy panel must complete a
6 to 12 month course of isoniazid if recommended by an infectious disease consultant.
Pregnant women, nursing mothers or individuals (men and women) not practicing birth
Uncontrolled hypertension, defined as BP greater than 140/90 on greater than 25% of
measurements. Blood pressures will be measured 3 times at each clinic visit after the
patient has sat quietly for at least 5 minutes. Thus at least 6 BP determinations will be
recorded prior to initiating sirolimus therapy.
Chronic liver disease sufficiently severe to impair sirolimus metabolism; this would
include prolonged pro-thrombin time. Patients with abnormal liver function tests will be
evaluated by the Hepatology Consult Service to determine whether protocol participation is
Basal thrombocytopenia less than 100,000 cells/microliters or absolute neutrophil count
less than 2000 cells/microliters or hematocrit less than 30.
Cancer diagnosis or cancer recurrence within the preceding 5 years, excluding basal cell
carcinoma of the skin.
Routine use of NSAIDS, defined as NSAID use more than two doses a week.
Clinically significant medical conditions, which in the opinion of the investigators, could
increase the subject s risk of participating in the study or could confound the
interpretation of the results of the study.