Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy

This is a pilot intervention study to evaluate preliminary evidence of the safety and
effectiveness of a novel combination immunosuppressive regimen, Rituximab plus cyclosporine,
in the treatment of idiopathic membranous nephropathy. Membranous nephropathy is a condition
that affects the kidney and involves damage to the walls of tiny blood vessels filters in the
kidneys called glomeruli. This damage allows blood proteins to leak into the urine
(proteinuria). As a result, patients have low protein levels in the blood, high blood
cholesterol levels and often develop leg swelling. This combination of symptoms and signs is
called the nephrotic syndrome. Some patients with membranous nephropathy develop impaired
kidney function and a proportion of these patients may develop kidney failure. The
immunosuppressive drugs that are most often used to treat membranous nephropathy include
cyclophosphamide plus steroids or cyclosporine. These vary in their effectiveness among
patients and there are side effects with each treatment. Rituximab alone has been used
experimentally to treat membranous nephropathy in small clinical trials. It has been
associated with decreased proteinuria of variable degrees in some patients.

The purpose of this pilot study is to evaluate whether the combination of Rituximab plus
cyclosporine, two drugs with different effects on the immune system, results in a greater
number of remissions of the nephrotic syndrome and more sustained remissions than is expected
with cyclosporine alone. Although each of these medications has been used separately in
membranous nephropathy, the potential benefits and risks of this combination have not yet
been formally explored.

Patients age 18 years and older with idiopathic membranous nephropathy will be eligible to
participate in this study. Pregnant and nursing women may not participate. Candidates must
have persistent nephrotic syndrome despite a 6 month observation period and treatment with
angiotensin converting enzyme inhibitors or angiotensin receptor blocker. Candidates will be
screened with a medical history, physical examination, blood and urine tests, review of the
medical records and kidney biopsy results.

Participants will come to NIH in Bethesda, Maryland for evaluation and to receive intravenous
infusions of Rituximab. Two doses of Rituximab will be given (2 weeks apart). Participants
will also take cyclosporine pills twice a day. After 6 months, the dose of cyclosporine will
be tapered over several weeks and then discontinued. Patients will be re-treated with a
second course of Rituximab (two infusions given two weeks apart) after a minimum of 6 months
has passed since completing the first course of Rituximab. The exact timing of the second
course of Rituximab will depend on the results of blood tests. All patients will be followed
for a minimum of 24 months from the time that therapy is initiated.

- INCLUSION CRITERIA:

1. Ability and willingness to provide informed consent (adults greater than or equal
to18 years).

2. Nephrotic range proteinuria that persists for at least 6 months greater than 3.5
grams /24 hours (based on 24 hour urine collection).

3. Nephrotic range proteinuria (>3.5 g/24 hours) that persists despite angiotensin
antagonist therapy (ACE inhibitor or ARB) for at least 2 months unless
intolerant.

4. Renal biopsy within the past 24 months must reveal typical changes of membranous
nephropathy by light and electron microscopy.

5. There is no evidence to suggest secondary forms of membranous nephropathy.
Diagnostic studies for the common causes of membranous nephropathy are listed
under Baseline evaluation. Additional studies will be obtained as indicated.

EXCLUSION CRITERIA:

1. Age <18 years old

2. Estimated GFR<40 ml/min/1.73 m^2 (determined by the 4 variable version of the MDRD
Study prediction equation) while on ACEI/ARB therapy . Lab values from the preceding 2
months prior to enrollment will be used to assess eligibility.

3. Immunosuppressive medications or experimental medications of any type during the three
month period prior to initiating Rituximab and cyclosporine.

4. Prior exposure to cyclosporine or tacrolimus for more than 6 months and/or evidence of
intolerance or toxicity associated with cyclosporine treatment of any duration
including irreversible azotemia, liver dysfunction or hypertension.

5. Prior treatment with Rituximab.

6. Clinically significant medical conditions (i.e. severe heart failure NYHA class IV,
uncontrolled coronary artery disease/unstable angina), which in the opinion of the
investigator, could increase the subject s risk of participating in the study or could
confound the interpretation of the results of the study. Patients with a history of
arrhythmias will be evaluated by a cardiology consultant regarding recommendations as
Rituximab has been reported to exacerbate arrhythmias (in patients with rheumatoid
arthritis).

7. Active acute or chronic infection requiring antimicrobial therapy or serious viral
infection (HIV, hepatitis B or C, herpes simplex, varicella zoster virus, parvovirus).

8. Live viral vaccines within one month prior to Rituximab.

9. Pregnant women, nursing mothers or individuals (men or women) not practicing birth
control.

10. Uncontrolled hypertension defined as BP >140/90 on >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.

11. Cancer diagnosis or cancer recurrence within the preceding 5 years, excluding basal
cell carcinoma of the skin.

12. Clinical evidence of cirrhosis or chronic active liver disease sufficiently severe to
impair cyclosporine metabolism; this would include a prolonged prothrombin time.
Patients with abnormal liver function tests will be evaluated by the Hepatology
Consult Service to determine whether protocol participation is appropriate.

13. Cytopenia (neutrophils <1500/mm^3 and/or thrombocytopenia <75,000) and/or CD4 T cell
count <200/mm^3).

14. Diabetes mellitus.