• Effectiveness of B-cell depletion by anti-CD20 mAb in reducing progression of chronic renal allograft dysfunction by chronic humoral rejection, as assessed by difference in change in measured GFR [ Time Frame: At 24 months ] [ Designated as safety issue: No ]
  

• Patient survival [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
  
• Incidence of graft loss [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Incidence of biopsy-proven post-transplant lymphoproliferative disease (PTLD) [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  
• Decrease in circulating anti-HLA antibodies [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Loss of peritubular capillary (PTC) C4d staining on renal biopsy [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Degree and duration of B-cell depletion [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Frequencies of alloreactive T cells determined by ELISPOT [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Intragraft analysis of lineage specific markers and immunohistology to look at cellular infiltration [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Viral replication of polyoma virus, Epstein-Barr virus, and cytomegalovirus measured by PCR [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  

Organ rejection occurs when a patient's body does not recognize the new organ and attacks it. Data suggest that the development of anti-human leukocyte antigen (HLA) antibodies is an early clinical indication that organ rejection may occur. Rituximab is a genetically engineered monoclonal antibody directed against the CD20 antigen on B cells and is known to deplete B cells when administered intravenously; it is FDA-approved for the treatment of non-Hodgkin's lymphoma. In a previous small study, kidney transplant patients with either acute humoral rejection (AHR) or chronic humoral rejection (CHR) were given rituximab and other antilymphocyte therapy. Patients with AHR had lower or undetectable levels of circulating anti-HLA antibodies after study treatment, and patients with CHR had a sustained decrease of anti-HLA antibodies to undetectable after 6 to 9 months. This new study will evaluate the safety and efficacy of rituximab in preventing organ rejection and promoting long-term survival of donor kidneys in people who undergo kidney transplantation.

The study will last 8 years. The study will enroll participants for 3 years, and patients will participate in the study for 2 to 5 years. This study involves two stages.

Stage 1 begins 3 to 36 months after transplant. During Stage 1, blood collection will occur every 3 months for up to 36 months after transplant to test for anti-HLA antibodies. When these antibodies are detected twice within 1 month, the patient will undergo a baseline kidney biopsy and have his or her glomerular filtration rate (GFR) measured to determine kidney function. If a patient meets certain study criteria, he or she will enter Step 2.

If anti-HLA antibodies are not detected in a patient's blood during Stage 1, the patient's participation will be complete.

In Stage 2, patients will be randomly assigned to one of two study treatment groups:

• Group 1 adult participants, 18 years of age or older, will receive an intravenous infusion of 1000mg of rituximab at Days 0 and 14. Group 1 pediatric participants, 18 years of age or younger, will receive an intravenous infusion of 375 mg/m2 of rituximab at Days 0, 8, 15 and 22.
• Group 2 adult participants, 18 years of age or older, will receive an intravenous infusion of 1000mg of placebo at Days 0 and 14. Group 2 pediatric participants, 18 years of age or younger, will receive an intravenous infusion of 375 mg/m2 of placebo at Days 0, 8, 15, and 22.

All participants will also receive standard of care immunosuppressive drugs. Adult participants, 18 years of age or older, will have 9 study visits over 24 months. Pediatric participants, 18 years of age or younger, will have 11 study visits over 24 months. A physical exam, medication history, adverse events assessment, and blood and urine collection will occur at all visits. A biopsy of the kidney transplant will occur at Stage 2 entry and Month 24.