Inclusion Criteria:
Renal Histology-Entry Criteria:
Note: All eligible patients will have undergone a renal biopsy compatible with a diagnosis of IgA nephropathy within 3 months of study entry. The diagnostic criteria for IgA nephropathy are as follows:
- Light microscopy demonstrating mesangial matrix expansion with mesangial cell hypercellularity defined as 5 or more mesangial cells per stalk
- Mesangial immunohistologic staining that is positive for IgA antibodies and is considered by the renal pathologist to be predominant over concurrent staining for IgG and IgM
- Presence of mesangial immune complexes on electron microscopy with or without the presence of podocyte foot plate effacement.
- To be eligible for study participation, endocapillary proliferation, karyorrhexis or cellular crescents must be presence in less than 10% of glomeruli on initial renal biopsy.
Clinical Criteria:
- Any patient 18 years of age or older and able to give informed consent and having proteinuria (> 1000 mg/24 hrs without ACE/ARB therapy; > 500 mg/24 hours on ACE or ARB therapy) with biopsy proven IgA nephropathy and the histologic features outlined in sections A, B &C of section 3.1.1 will be considered eligible for study enrollment. Patients must be between the ages of 16 and 70 for all sites except Stanford University. The eligible age range at the Stanford University site will range from age 5-70. Patients must be able to give informed written consent. If the patients is less than 18 but older than 16, they can participate in the study provided that a parent or guardian signs an age-appropriate consent. For patient being enrolled at the Stanford University site any patient age 5 years or greater with parental permission may be included in the study.
(For Stanford University site only: Stanford has extensive experience with pediatric, as young as one year of age, use of Rituximab in acute renal transplant rejection therefore request that the patients must be between the ages of 5 and 70.)
- Renal Insufficiency: Patients with stage II or III Chronic Kidney Disease (CKD) with estimated GFR by Cockgault-Gault or MDRD equations < 90 mls/min and > 30 mls/min.
- Proteinuria: Patients excreting greater than or equal to 1000 mg of proteinuria/24 hours while on stable ACE or ARB therapy for 2 months. Patients receiving combination ACE or ARB will only require 500 mg/24 hours for study eligibility.
- Hypertension: Any patient requiring long-term hypertensive medications or a mean arterial pressure (MAP) greater than 105 off medication must be present to be considered eligible for the study .
- Gender: Female patients with IgA nephropathy will be considered eligible for study entry if they have a negative urine or serum pregnancy test at the time of screening. Patients wishing to be enrolled in the study must also be agreeable to 2 years of contraception.
- Henoch Schonlein Purpura (HSP): Patients with biopsy proven IgA nephropathy and clinical features consistent with Henoch Schonlein Purpura will be considered eligible for the study.
- Patient must be able to swallow the oral medications to be enrolled in the study.
Exclusion Criteria:
- Clinical and histologic evidence of IgA predominant Lupus nephritis.
- Clinical and histologic evidence of idiopathic IgA forms of membranoproliferative glomerulonephritis.
- Clinical evidence of cirrhosis or chronic active liver disease.
- Estimated GFR <30 ml/min/1.73m2 at the time of screening.
- Patients with greater than 50% glomerular senescence or cortical scarring on renal biopsy.
- Active systemic infection or history of serious infection within one month of entry.
- Known infection with HIV, hepatitis B or hepatitis C (patients will be serologically screened prior to study entry).
- Patients with Child’s Class C Cirrhosis.
- Patients with history of Crohn’s disease or Celiac Sprue
- Positive pregnancy test or breast feeding at time of study entry. Patients unwilling to comply with contraceptive measures as outlined above.
- Current or recent (within 30 days) exposure to any investigational drug.
- Serum Cr > 3.5 mg/dl or MDRD calculated GFR < 30 mls/min.
- Patients receiving > 6 months therapy with oral prednisone or glucocorticoid equivalent.
- Patients having received a live vaccine within 28 days of study enrollment will be excluded from study.
General Safety & Laboratory Exclusion Criteria
- Patients with anaphylaxis and/or known allergic reactions to Rituximab
- Hemoglobin: < 8.5 gm/dL
- Platelets: < 100,000/mm
- AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.
- Receipt of a live vaccine within 4 weeks prior to randomization
- Previous Treatment with Rituximab (MabThera® / Rituxan®)
- Previous treatment with Natalizumab (Tysabri®)
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
- History of recurrent significant infection or history of recurrent bacterial infections
- Known active bacterial, viral fungal mycobacterial or atypical mycobacterial infections, but excluding fungal infections of nail beds).
- Any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
- Ongoing use of high dose steroids (>10 mg/day) or unstable steroid dose in the past 4 weeks
- Lack of peripheral venous access
- History of drug, alcohol, or chemical abuse within 6 months prior to screening
- Pregnancy (a negative serum or urine pregnancy test will be performed for all women of childbearing potential no later than 7 days prior to treatment) or lactation
- Concomitant or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
- History of psychiatric disorder that would interfere with normal participation in this protocol
- Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication
- Inability to comply with study and follow-up procedures
Purpose
