Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

Study Overview
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Brief Summary
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Current therapy to prevent organ rejection relies on the use of calcineurin inhibitors either cyclosporine or tacrolimus. Although these agents have been very successful in preventing early acute rejection, this success has not translated into improved long-term kidney transplant function. One of the important factors that leads to premature kidney transplant failure is chronic allograft nephropathy (CAN). CAN is characterized by progressive interstitial fibrosis or scarring, vascular wall thickening, and finally glomerular sclerosis leading to slow progressive loss of kidney function. Calcineurin inhibitors have been shown to play an important role in the pathogens of CAN. Renal transplant recipients in whom calcineurin inhibitors are discontinued enjoy better and longer kidney function. Therefore, immunosuppressive strategies are being designed with the intention of withdrawing calcineurin inhibitors. The purpose of this trial is to test if tacrolimus can be safely substituted by sirolimus (Rapamycin) and this substitution will yield improved renal function, less CAN and better graft survival rates over the first year.

Detailed Description
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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.

Official Title
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Phase 4 Study: Comparison of Myfortic and Early Rapamycin Conversion vs. Low-Dose Tacrolimus in Preventing Acute Rejection and Chronic Allograft Fibrosis: A Protocol Biopsy Directed Approach

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Procedure: Kidney Biopsy
* Drug: Rapamune (sirolimus/rapamycin)
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. Low-dose tacrolimus arm<br>Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months). All patients will undergo a second protocol biopsy at 12 months. | Procedure: Kidney Biopsy<br>* Skin over the kidney will be cleansed and disinfected. The skin and deeper tissue will be numbed with novocaine like solution. A special needle will be inserted guided by ultrasound into the kidney for an instant to withdraw the small specimen.<br>Drug: Tacrolimus<br>* Patients in this group will continue to receive tacrolimus at reduced doses. Doses will be titrated to achieve tacrolimus trough blood levels between 4 and 6. Myfortic at doses of 720 mg BID and steroids will be continued for the duration of the study (12 months).<br>|
| Experimental: 2. Rapamune conversion arm:<br>Patients in this group will undergo a gradual conversion from tacrolimus to Rapamune therapy. Tacrolimus will be withdrawn progressively over a period of 7-10 days. Dosage adjustments will be made with the aim of reducing the blood levels of tacrolimus by 25% every other day until tacrolimus is discontinued. Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study. | Procedure: Kidney Biopsy<br>* Skin over the kidney will be cleansed and disinfected. The skin and deeper tissue will be numbed with novocaine like solution. A special needle will be inserted guided by ultrasound into the kidney for an instant to withdraw the small specimen.<br>Drug: Rapamune (sirolimus/rapamycin)<br>* Rapamune will be given at a dose of 5mg/day for two days beginning at the initiation of tacrolimus reduction. Thereafter, Rapamune will be given at a dose of 3 mg/day. The dose of Rapamune will be titrated to achieve a blood level (by HPLC) between 5 and 10 for the duration of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Graft Survival at 12 Months | Graft survival is defined as no rejection or inflammation at 12 months. | Number of participants biopsied at 12 months post-transplant | 
| Either Equivalent or Improved Estimated Glomerular Filtration Rate (eGFR) at One Year in the Rapamycin Group | Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula. | 1 year post-transplant | 
| Improved Histology at 12 Months in the Rapamycin Group | Chronic allograft damage index (CADI) scores. It's a sum score of six histo- pathological lesions commonly seen in biopsies taken from transplanted kidneys that correlate with the function and outcome of the graft. The maximum CADI score can go up to 18. In this case the lesions found were Interstitial fibrosis (IF) and Tubular Atrophy (TA) subscales from 0 (min) to 5 (max) . A score of 0 to 1 means absence of chronic allograft damage, a score of 4 is severe damage. . | 3 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Transplant, Immunosuppression drugs, Rapamune, tacrolimus, calcineurin inhibitor, Kidney Biopsy, Needle