Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression-
Condition: Kidney Transplant
Intervention: Sirolimus; Tacrolimus
Intervention description: Tacrolimus to Sirolimus; dosage per trough level
Intervention MeSH terms: Sirolimus; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Kidney transplant

Summary:

      The investigators hypothesize that Tacrolimus (Tac) withdrawal from a Tac, MMF and steroid
      based triple therapy regimen leads to long term improved/stabilized graft function
      (glomerular filtration rate, GFR) primarily as a consequence of halting CNI-induced
      fibrogenetic processes that mediate loss of functioning renal tissue. The investigators
      further hypothesize that the underlying fibrotic mechanism is mediated by pathophysiologic
      processes that promote epithelial to mesenchymal transition (EMT) (mediated by TGF- ƒÒ) and
      that early therapeutic intervention may reverse this process (mediated by BMP-7)4.

      To address these hypotheses the investigators propose the following clinical and mechanistic
      aims:

      The investigators will test the hypothesis that switching from Tac to SRL in a Tac based
      triple therapy regimen with MMF and steroids in living and or deceased donor renal transplant
      recipients leads to improvement in allograft structure and function at 2 years
      post-transplantation.

      The investigators will test this hypothesis in an open label controlled trial where stable
      renal allograft recipients on Tac, MMF, prednisone maintenance immunosuppression will undergo
      renal biopsy at 3-4 months post-transplantation and will be randomized to either a) Remain on
      Tac, MMF and prednisone (CNI-maintenance) or b) switch the Tac to SRL and continue MMF and
      prednisone. The investigators will then compare biopsy derived measures of allograft fibrosis
      (CADI, Sirius Red, Banff Chronicity Index) and GFR in the two groups
    

Eligibility criteria:

        Inclusion Criteria:

          1. Absence of clinical acute rejection in post-transplant period preceding randomization

          2. HLA-mismatched solitary first and second kidney transplant recipients

          3. Absence of any degree of rejection (Banff 2007) on renal biopsy at 3-6 months(+/- 2
             months) post-transplant.

          4. Absence of post-transplant donor-specific antibody

        Exclusion Criteria:

          1. HLA-identical transplants

          2. Contraindication or inability to undergo renal biopsy, like previous complications due
             to biopsies, anticoagulation, active infection, etc.

          3. Positive flow cross match, sensitized recipient, presence of donor-specific antibody.

          4. Rejection episode after transplantation, either cellular or humoral on for cause or
             renal biopsy.

          5. Rejection present on pre-randomization renal biopsy.

          6. Proteinuria greater than 0.3 gram/day

          7. Native kidney disease biopsy proven or likely glomerulonephritis, primary or recurrent
             FSGS, MPGN or primary or recurrent membranous GN.

          8. Hypertriglyceridemia > 400 mg/dL (treated), LDL cholesterol > 160 mg/dL while on
             optimal treatment.

          9. WBC < 2000/mm3, ANC < 1000 mm3, Platelet count < 100,000 mm3

         10. Active wound issues.

         11. Primary non-function.

         12. Active BKV or CMV disease.

         13. Evidence of recurrent disease.

         14. Active infection

         15. Pregnancy

         16. Women of childbearing potential unable or unwilling to use birth control during the
             study.

         17. e GFR ≤ 40 ml/ min at screening