Overview

Background

• Membranous nephropathy is associated with damage to the walls of the glomeruli, the small blood vessels in the kidneys that filter waste products from the blood. This damage causes leakage of blood proteins into the urine and is associated with low blood protein levels, high blood cholesterol values, and swelling of the legs. These problems can decrease or go away without treatment in about 25 percent of patients, but if they persist, some patients may experience impaired (or loss of) kidney function, blood vessel and heart disease, and a risk of forming blood clots in veins.
• Kidney biopsies that show that antibodies have been deposited along the glomeruli suggest that specialized cells of the immune system, called B and T cells, are causing damage to the kidneys through their increased activity. To suppress the action of B and T cells and to decrease the harmful deposits in the kidneys, drug treatments are required.
• Patients with membranous nephropathy are often treated with immunosuppressive drugs such as cyclosporine or cytoxan plus steroids that attempt to reduce or suppress the activity of the immune system, decrease antibody production, and reduce antibody deposits in the kidney. However, not everyone responds to these medications and the kidney disease can return in some patients when the drugs are stopped. Also, there are side effects associated with long term usage of these medications. Rituximab, a different immunosuppressant, has also been used for this purpose. Although cyclosporine and Rituximab have been used separately, they have not been tried in combination as a possible treatment for membranous nephropathy.

  Objectives

• To determine the safety and effectiveness of combining rituximab and cyclosporine to treat membranous nephropathy.

  Eligibility

• Individuals 18 years of age and older who have been diagnosed with membranous nephropathy based on a kidney biopsy done within the preceding 24 months, and who have had excess levels of protein in the urine for at least 6 months based on urine and blood tests.

  Design

• Potential participants will be screened with an initial clinic evaluation and full medical history.
• Before the treatment, there will be a run-in period that will last up to 2 months. During this time, participants will be placed on a blood pressure lowering medication and will not take any other immunosuppressant medications.
• Participants will visit the NIH clinical center for a baseline evaluation, four intravenous infusions of rituximab, and also at 1- to 6-month intervals throughout the study.
• Active treatment period will involve a 6-month course of cyclosporine and a total of four doses of rituximab. Participants will take cyclosporine tablets twice daily, and have two infusions of rituximab given 2 weeks apart, After 6 months, the cyclosporine dose will slowly be decreased over several weeks and then completely discontinued. Participants will then receive another course (two doses 2 weeks apart) of rituximab, depending on results of blood work.
• Participants will have frequent blood and urine tests performed to monitor the results of treatment and reduce the chance of side effects.

Eligibility

• INCLUSION CRITERIA:

        In order to be eligible to participate in this study, an individual must meet all of the
        following criteria:
          1. Stated willingness to comply with all study procedures and availability for the
             duration of the study
          2. Male or female, >= 18 years of age
          3. Nephrotic range proteinuria that persists for at least 6 months post diagnosis of
             membranous nephropathy greater than 3.5 grams /24 hours (based on 24-hour urine
             collection).
             a. If the subject s renal function rapidly declines in less than 6 months could
             proceed with immunosuppression therapy sooner such as complications of the nephrotic
             syndrome that are not controlled with supportive therapy or evidence of decline in
             glomerular filtration rate or proteinuria >8 grams/day. Subjects with declining renal
             function and/or high-grade proteinuria due to MN are considered "high risk" subjects
             and have a higher probability of progression to end stage kidney disease.
          4. 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.
             a. The rationale is that blockade of the renin angiotensin system (RAAS) is widely
             considered to be part of the standard of care treatment for subjects with the
             nephrotic syndrome. Nephrotic range proteinuria will be defined as an estimated
             average proteinuria >3.5 g/24 hours in adults based on at least two 24-hour urine
             protein excretions obtained prior to initiating therapy. Incomplete urine
             collections (based on inadequate creatinine excretion) will be excluded.
          5. Renal biopsy within the past 24 months must reveal typical changes of membranous
             nephropathy by light and electron microscopy or a positive anti-PLA2R antibody test in
             the serum. There has been a change in the management strategies for MN such that a
             renal biopsy is not absolutely required for diagnosis if patient has positive
             circulating anti-PLA2R antibody.
             a. Based on published KDIGO 2021 Clinical Practice Guidelines 3.1.1 patients with MN
             who are positive for anti-PLA2R do not require renal biopsy as long as renal function
             is normal (eGFR >60) and has not had immunosuppression as it has been demonstrated
             that results of the biopsy have not altered clinical approach and management. If not
             PLA2R positive, renal biopsy within 24 months is still required.
          6. Blood pressure <=140/90 on >75% of measurement while on anti-hypertensive treatment
             for at least 1-2 months.
          7. There is no evidence to suggest secondary forms of membranous nephropathy.
          8. Ability to take oral medication and be willing to adhere to the cyclosporine regimen
          9. For females of reproductive potential: use of highly effective contraception for at
             least 1 month prior to screening and agreement to use such a method during study
             participation and for 12 months after the last Rituximab infusion.
         10. For males of reproductive potential: use of condoms or other methods to ensure
             effective contraception with partner.
         11. Ability of subject to understand and the willingness to sign a written informed
             consent document.
        EXCLUSION CRITERIA:
        An individual who meets any of the following criteria will be excluded from participation
        in this study:
          1. Estimated GFR<40 ml/min/1.73 m^2 from the preceding 2 months prior to enrollment while
             on ACEI/ARB therapy.
          2. Immunosuppressive medications or experimental medications of any type during the
             three-month period prior to initiating Rituximab and cyclosporine.
          3. 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
          4. Rituximab use within the previous 12 months.
          5. 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.
          6. Positive HIV serology
          7. Positive HCV serology
          8. Active acute or chronic infection requiring antimicrobial therapy or serious viral
             infection cytomegalovirus, herpes simplex, varicella zoster virus (chicken pox or
             shingles), Parvovirus B19 (can be based on previous medical records within the past
             24-months)
          9. Live viral vaccines within one month prior to Rituximab.
         10. Pregnancy or lactation
         11. Cancer diagnosis or cancer recurrence within the preceding 5 years, excluding basal
             cell carcinoma of the skin. The rationale is that immunosuppression may accelerate
             cancer progression.
         12. Clinical evidence of cirrhosis or chronic active liver disease sufficiently severe to
             impair cyclosporine metabolism; this would include a prolonged prothrombin time.
         13. Cytopenia (neutrophils <1500/mm^3 and/or thrombocytopenia <75,000) and/or CD4 T cell
             count <200/mm^3). The rationale is that Rituximab therapy may be followed by cytopenia
             with the granulocyte lineage being at greatest risk. Patients with low CD4 T cell
             counts are prone to infection which can be exacerbated by Rituximab.
         14. Diabetes mellitus. The rationale is that diabetes may lead to worsening of proteinuria
             that would not respond to immunosuppression and would confound the results.