Obinutuzumab in Primary MN

Inclusion Criteria:

1. Adults (≥18 years old) on the day of signing informed consent.

2. Biopsy-proven primary membranous nephropathy.

3. Availability of a recent (over the last six months) diagnostic kidney biopsy toconfirm the diagnosis of membranous nephropathy and quantify the severity of chronicchanges and the number of glomerular podocytes.

4. High-risk of progression to end-stage kidney disease due to persistentnephrotic-range proteinuria (urinary protein excretion > 3.5 g/24-hours as a medianof three consecutive measurements) despite background treatment with RAS-inhibitors (ACEi and/or ARBs) at the maximum tolerated doses for at least six months beforeinclusion.

5. Failure to definitively and effectively respond to rituximab therapy because of thefollowing:

6. RITUXIMAB-INTOLERANCE, i.e. any previous severe hypersensitivity reaction torituximab (acute grade III or IV adverse reactions requiring advanced care, orlate reactions including delayed serum sickness syndrome) that, independent ofresponse to treatment, preclude further exposure to the drug; or

7. RITUXIMAB-RESISTANCE: no evidence of nephrotic syndrome complete remission (24-hour proteinuria < 0.3 g/day, normal serum albumin and stable renalfunction) or partial remission (24-hour proteinuria < 3.5 g/day with > 50%decrease from baseline, normal serum albumin and stable renal function) alongwith detectable circulating CD19+ lymphocytes for at least 6 months afterrituximab administration or

8. RITUXIMAB-DEPENDENCE: frequently-relapsing nephrotic syndrome (≥ 2 relapses)with nephrotic-range proteinuria for ≥ 50% of time in the 24 months precedingenrolment initial remission after rituximab administration

9. Estimated GFR/eGFR) ≥30 mL/min/1.73 m2 (calculated using the CKD-EPI equation) orqualified endogenous creatinine clearance ≥30 mL/min/1.73 m2 based on 24-hour urinecollection during screening.

10. Ability to understand and provide a valid written consent to the study according tothe guidelines of the Declaration of Helsinki.

11. Compliance with an effective contraception without interruption, from 28 days beforetreatment start up to 18 months after treatment discontinuation, agreeing not todonate semen during treatment and for 18 months after discontinuation (if thepatient is male), or to undergo pregnancy test during the course of the study (ifthe patient is female). (According to 2014 CTFG "Recommendations related tocontraception and pregnancy testing in clinical trials").

Exclusion criteria:

1. Secondary forms of membranous nephropathy (associated with systemic lupuserythematosus, active hepatitis B, malignancy, drugs such as gold salts andpenicillamine, and others).

2. Rituximab treatment or any other prolonged (i.e. for more than two weeks)immunosuppressive treatment in the 6 months preceding anti-CD20 infusion.

3. Uncontrolled hypertension (systolic BP ≥160 and/or diastolic BP >90 mmHg despitetherapy).

4. Active bacterial, viral and/or fungal infections.

5. Seropositivity for HIV, regardless of viral load.

6. Active or recent (< 5 years before enrolment) history of malignancy.

7. Known hypersensitivity or allergy to any of the medicaments under investigation.

8. Any other serious medical condition, uncontrolled intercurrent illness or laboratoryabnormality that, according to the investigator's judgement, would constitute anunacceptable risk of premature discontinuation from the study.

9. Patients with previous hepatitis B virus infection (seropositive for anti-HBcAb),planning a vaccination with live virus vaccines

10. Known history of drug induced liver injury, alcoholic liver disease, non-alcoholicsteatohepatitis, primary biliary cirrhosis, ongoing extra-hepatic obstruction causedby cholelithiasis, cirrhosis of the liver or portal hypertension.

11. Pregnancy or breast-feeding

12. Childbearing potential and unwillingness or impossibility to comply with ascientifically acceptable birth-control method (According to 2014 CTFG "Recommendations related to contraception and pregnancy testing in clinicaltrials").

13. Legal incapacity, limited legal capacity, intellectual disability, uncooperativeattitude or any other evidence that the patient will not be able to understand thestudy aims and procedures.