Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

The purpose of this study is to determine if tacrolimus can be safely lowered to potentially non-nephrotoxic levels or discontinued completely in favor of Rapamycin 3 months after kidney transplantation. In this study, all patients will be maintained on full-dose (720 mg BID) mycophenolate sodium (Myfortic) to ensure adequate immunosuppression. In addition, we will compare the immunosuppressive regimens of Rapamune/mycophenolate sodium/Prednisone to Low-Dose Prograf/ mycophenolate sodium /Prednisone for their long-term effects on renal function, cardiovascular risk factors, subclinical rejection and chronic allograft fibrosis.

We also plan to examine the clinical benefit of protocol biopsies. The first protocol biopsy would occur at the time of implantation. This would provide an assessment of the state of the donor kidney. The severity of donor disease would provide a baseline to which all subsequent biopsies can be compared. The second protocol biopsy would be performed at the time of tacrolimus withdrawal. Patients found to have subclinical rejection on this biopsy would not undergo tacrolimus withdrawal but may benefit from increased immunosuppression. The protocol biopsy would provide an additional level of safety ensuring that only "low-risk" (histologically) patients undergo tacrolimus withdrawal. A third biopsy would be performed one year after transplantation. Renal allograft tissue would be examined for the presence of progressive fibrosis or persistent subclinical rejection both of which lead to graft failure. The efficacy of tacrolimus withdrawal can be assessed using both clinical and pathologic criteria.

A third aim of this trial is to examine whether changes in immunosuppressive therapy leads to differential expression of immunological markers or serum mediators such as cytokines. Recent studies suggest that, in vitro, thymoglobulin induces the generation of "regulatory" cells. This study will examine the in vivo relevance of this novel observation. In addition, we will measure the circulatory mediators of renal fibrosis to examine if the two treatment arms differ in their effects on such cytokine/growth factors. Blood samples will be collected and the PBMC will be analyzed by FACS for their composition and the presence of cell surface antigens that may reflect a state of immunological regulation or "suppression". Tissue samples will be analyzed by immunohistochemistry for the presence of immunologically relevant cellular subtypes such as CD4/CD25 regulatory T cells. Serum samples will be collected and analyzed for cytokine or growth factor expression.

Inclusion criteria

• All patients receiving their first renal allograft transplant will be considered eligible for study
• Patients receiving both living and cadaveric donors will be eligible

Exclusion criteria

• If less than 18 years of age
• Severe hyperlipidemia
• If pregnant or cannot comply with proper birth control during the study
• Recipients of kidney together with another solid organ or bone marrow transplant
• Patients receiving any investigational medications or participating in a clinical trial
• Patients receiving a second or third renal allograft
• PRA > 30%
• Active infections
• Chronic antiarrhythmic therapy for ventricular arrhythmia
• Malignancy except for basal cell carcinoma
• HIV
• ANC count < 1,000/ mm3, Platelet count < 100,00/mm3
• Fasting triglycerides > 400 mg/dl and cholesterol > 300 mg/dl
• HCV-positive, HBVSAg-positive, HBVCoreAb-positive and HBVSAntibody negative or HCV/HBV co-infected patients
• Breastfeeding women