Rituximab Treatment to Block HLA Antibodies in Renal Transplant Recipients

Study Overview
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Brief Summary
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The purpose of this study is to determine if administration of rituximab blocks the development of donor specific antibodies (DSA) in transplant recipients who have developed renal dysfunction and DSA after renal transplant. It is hoped that by blocking DSA production renal function will stabilize or improve.

Detailed Description
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A long established risk factor for late renal allograft loss is the development of DSA. Recent studies from our group and others have shown that these antibodies are probably responsible for chronic rejection by attacking the vascular endothelium and fixing complement (detected as C4d in renal biopsies). Studies in humans and monkeys have shown that circulating antibody and complement deposition precede the development of chronic graft injury. Interruption of antibody production is a potential beneficial strategy to prevent late graft loss from this mechanism. Therapeutic regimens that have been used in an attempt to deplete HLA or ABO antibodies include plasmapheresis, IVIg, tacrolimus and mycophenolate mofetil (MMF), and anti-CD20 (rituximab). Of these regimens, the most specific is anti-CD20, rituximab (rituxan), a therapy now FDA approved for B cell proliferative diseases. Although initially introduced for the treatment of neoplasm, the humoral immunosuppressant effects of rituximab have been shown to have clinical significance. Rituximab interferes with both primary and secondary humoral responses by eliminating B-cells prior to antigen exposure, thus interfering with differentiation into antibody secreting cells and specific antibody production.

Official Title
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Pilot Study of Rituximab Treatment to Inhibit HLA Antibodies in Renal Allograft Recipients

Conditions
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Chronic Rejection, Kidney Insufficiency

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient of a primary cadaver or living donor renal allograft 18-64 years of age At least 6 months and no more than 10 years post renal transplant Serum clearly positive for defined DSA Renal biopsy positive for C4d staining within 28 days before study Day 1 treatment Blood positive for Cd 19/20 cells at greater than/equal to 50 % of lower limit of normal Baseline serum creatinine 1.7-3.0 mg/dl On stable doses of tacrolimus and MMF for at least 1 month prior to study entry Able and willing to sign IRB approved consent form and comply with the requirements of the screen, treatment and follow-up phase of the protocol Negative serum pregnancy test (women of child bearing potential) Men and women of reproductive potential agree to use an acceptable method of birth control during treatment, for twelve months after treatment completion, or until B cell counts return to normal, whichever is longer Exclusion Criteria: Hemoglobin: < 8.5 gm/dL Platelets: < 100.00/mm White blood cell count: < 3000/mm3 AST or ALT . 2.5 x Upper Limit of Normal unless related to primary disease Positive Hepatitis B or C serology History of positive HIV Treatment with any investigational agen within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer) Receipt of a live vaccine within 4 weeks prior to study entry Previous treatment with rituximab (rituxan) History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies History of recurrent infections Known active bacterial, viral, fungal, mycobacterial or other infection or any major episode of infection requiring hospitalization or treatment with intravenous antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening Ongoing use of high dose steroids (>10mg/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 screen Pregnancy or lactation Concomitant malignancies or previous malignancies History of psychiatric disorder that would interfere with normal participation in this protocol Significant cardiac or pulmonary disease Any other disease, metabolic dysfunction, physical examination finding or clinical lab finding giving reasonable suspicion of disease or condition that contraindicates use of an investigational drug or that may affect the interpretation of the results or render subject a high rist from treatment complications Inability to comply with study and follow-up procedures

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>this study has only one arm as the treatment group | Drug: Rituximab<br>* All subjects will be treated with Rituximab 1000 mg (1 g) intravenously on days 1 and 15.<br>* Other names: Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Negative DSA by Luminex beads or ELISA |  | at 12 months post study medication | 
| Lack of C4d deposition in peritubular capillary |  | on 12 month renal biopsy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Renal allograft function: Serum creatinine, Calculated creatinine clearance, Urine protein, Urine protein-creatinine ratio |  | 12 months after study entry compared to the baseline | 
| Change in chronic rejection pathology indices |  | on 12-month renal biopsy compared to baseline biopsy. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney transplantation, HLA