Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized Controlled Trial of Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy
Brief Summary: Idiopathic Membranous nephropathy (IMN) is an auto-immune glomerular disease. Recent studies suggest that circulating auto-antibodies against the podocyte surface antigens phospholipase A2 receptor1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) cause the disease in the majority of the patients. Additional autoantibodies, directed to podocyte neo-expressed cytoplasm proteins have been described, including aldose reductase (AR), Mn-superoxide dismutase (SOD2) and alpha-enolase (alpha-ENO).

The commonest presentation of IMN is nephrotic syndrome. Data from placebo arms of interventional studies show that 30-40% of the untreated patients with persistent nephrotic syndrome (NS) progress to end-stage renal disease (ESRD).

The best-validated treatment regimen of IMN is combination therapy with steroids and cyclophosphamide, capable to induce remission of protenuria in two-third of the patients.

Despite this evidence of efficacy, there are concerns about the use of cyclophosphamide, since it may be associated with adverse events, including bone marrow suppression, gonadal toxicity, infections and oncogenic effects. Thus, the availability of alternative therapies highly effective but with a greater safety profile is desirable.

Given the key role of IgG antibodies in IMN, B cell depletion may favourably impact the glomerular disease. The anti-CD20 monoclonal antibody Rituximab is a selective B cell depleting agent. There is evidence that Rituximab is effective in the treatment of other diseases in which B cells play a key role, such as ANCA-related vasculitis. Observational studies in IMN provided encouraging data; in addition, the drug seems well tolerated.

Head-to-head comparisons between Rituximab and steroid plus ciclophosphamide in randomized clinical trials are missing.

The investigators propose this study in order to test, in a randomized controlled trial, the hypothesis that Rituximab is more effective than cyclical steroid/alkylating-agent therapy in inducing remission in patients with IMN and NS undergoing the initial treatment. In addition, the levels of the above-mentioned pathogenetic autoantibodies will be measured at baseline and during treatment. Finally, the study will compare the safety profile of steroid plus cyclophosphamide and Rituximab by evaluating the rate and severity of adverse events


Options:
A: Inclusion Criteria:

1. Patients with idiopathic membranous nephropathy
2. The duration of disease is less than twelve months
3. Patients with persistent proteinuria more than 8 grams per day
4. Patients who provided informed consent
5. The cases that satisfy more than three of following items even if proteinuria is less than 8 grams per day:

   * eGFR \< 60 ml/min/1.73m2
   * Hypertension (BP above 140/90mmHg or BP above 120/80 in patients taking anti-hypertensive agents)
   * 24 hours urine protein or spot urine protein/creatinine ratio \> 5.0 g/day
   * Serum albumin (g/dL) \< 3.0
   * Selectivity index \> 0.2

Exclusion Criteria:

1. Severe digestive organ disease
2. Allergy history to clinical trial medication and acute or chronic allergy for 4 weeks recently.
3. Clinical history of treatment with other immunosuppressive medication
4. Probability of pregnancy, breast feeding woman
5. Uncontrolled hypertension (more than 160/100mmHg)
6. Uncontrolled systemic disease
7. Drug addiction or alcoholics within 6 months
8. eGFR is less than 30ml/min at screening
9. Abnormal liver function test (more than 3 times above compared with normal value)
10. Absolute neutrophil count \<1,500/mm3 or leukocyte \<2,500/mm3 or platelets \<100,000/mm3
11. Secondary membranous nephropathy
12. Expected life expectancy is less than 1 year
B: Inclusion Criteria

* Idiopathic MN with diagnostic biopsy
* Female, must be post-menopausal, surgically sterile or practicing a medically approved method of contraception(no birth-control pill)
* Must be off prednisone or mycophenolate mofetil for \>1 month and alkylating agents for \>6 months.
* angiotensin-converting-enzyme inhibitor (ACEi) and/or Angiotensin II receptor blockers (ARB), for \>3 months prior to randomization and adequate blood pressure (target BP \<130/80 millimeter of mercury (mmHg) in \>75% of the readings, but subjects with BP \<140/80 mmHg in \>75% of the readings will be eligible). Patients with documented evidence of \>3 months treatment with maximal angiotensin II blockade, on an 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA) reductase inhibitor, and BP control (BP \<140/80 mmHg in \>75% of the readings) who remain with proteinuria \>5g/24h may enter and be randomized to RTX/CSA without the need of the run-in/conservative phase of the study.
* Proteinuria \>5g/24h on two 24-hour urine collection collected within 14 days of each other
* Estimated glomerular filtration rate (GFR) ≥40 ml/min/1.73m2 while taking ACEi/ARB therapy OR quantified endogenous creatinine clearance \>40 ml/min/1.73m2 based on a 24-hour urine collection.

Exclusion Criteria

* Presence of active infection or a secondary cause of MN (e.g. hepatitis B, systemic lupus erythematosus (SLE), medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred \<2 years prior to enrollment into the study.
* Type 1 or 2 diabetes mellitus: to exclude proteinuria secondary to diabetic nephropathy. Patients who have recent history of steroid induced diabetes but no evidence on renal biopsy performed within 6 months of entry into the study are eligible for enrollment.
* Pregnancy or breast feeding for safety reasons
* History of resistance to CSA (or other calcineurin inhibitors, e.g. tacrolimus), RTX or alkylating agents (e.g. Cytoxan). Patients who previously responded to CSA/Calcineurin Inhibitor (CNI), RTX or alkylating agents with either a complete remission (CR) or partial remission (PR) but relapsed off CSA/CNI after 3 months or relapsed off RTX or alkylating agent after 6 months are eligible.
C: Inclusion Criteria:

* At least 18 years old.
* Idiopathic Membranous nephropathy proved by renal biopsy
* Persistent urinary protein excretion rate ≥3,5g/24 h and albuminemia \< 30g/l for at least 6 months with full dose of NIST
* Patient receiving a non immunosuppressive conventional treatment (antiproteinuric and antihypertensive blocking the rennin-angiotensine system, lipid-lowering statin) since at least 6 months.
* Patient has given its written consent
* Patient with social coverage (excepting AME)
* Use of an efficient contraception method for women in childbearing age.

Exclusion Criteria:

* Secondary membranous nephropathy
* Patient already in a clinical trial
* Patient received an immunosuppressive treatment within 3 months before the study
* Patient with chronic renal disease defined by estimated GFR by MDRD formula under 30ml/mn/1,73m²
* Pregnancy and breastfeeding
* HIV infection, HCV and HBV active infection
* Severe or evolving infections.
* Allergy or hypersensitivity to Rituximab or any component
D: Inclusion Criteria:

1. Biopsy-proven diagnosis of idiopathic MN performed within the past 24 months
2. Proteinuria \> 3.5 g/24h on three 24-hour urine collection (once a week for 3 weeks)
3. Estimated GFR (MDRD formula) ≥ 30ml/min/1.73m2 under ACEI/ARB therapy
4. Post-menopausal females, or females surgically sterile or practicing a medically approved method of contraception (no birth-control pill)
5. Three months of ACEI and/or ARB therapy before treatment
6. Blood Pressure \<130/80 mm Hg
7. HMG-CoA reductase inhibitor therapy
8. Patients remaining with proteinuria \>3.5g/24h after 3 months of ACEI and/or ARB therapy and Blood Pressure \<130/80 mm Hg may be randomized to RTX / cyclical corticosteroid/alkylating-agent therapy without the need of the run-in/conservative phase of the study.

Exclusion Criteria:

1. serum creatinine \>2.5 mg/dl; Estimated GFR \< 30 ml/min/1.73m2
2. previous treatment with Rituximab, Steroids, Alkylating Agents, Calcineurin Inhibitors, Synthetic ACTH, MMF, Azathioprine
3. Presence of active infection
4. Secondary cause of MN (e.g. hepatitis B, SLE, medications, malignancies). Testing for HIV, Hepatitis B and C should have occurred \< 6 months prior to enrollment into the study
5. Type 1 or 2 diabetes mellitus
6. Pregnancy or nursing for safety reasons
7. Renal vein thrombosis documented prior to entry by renal US or CT scan

Answer: D