Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy

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.