Kidney Biopsy Controlled Trial of Calcineurin Inhibitor Withdrawal

Kidney Transplantation Clinical Trial

Official title: 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

Status Completed

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Kidney Transplantation

• NCT number: NCT00896012
• Study type: Interventional
• Source: University at Buffalo
• Status: Completed
• Phase: Phase 4
• Start date: January 2008
• Completion date: December 2011