Everolimus Plus Mycophenolic Acid for Kidney Preservation in Liver Transplant Recipients With Impaired Kidney Function
Condition: Kidney Failure
MeSH terms: Renal Insufficiency
Intervention: Tacrolimus; Everolimus
Intervention description: Low dose Tacrolimus; Everolimus
Intervention MeSH terms: Everolimus; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Tacrolimus as maintenance immunosuppression, then randomized to Everolimus plus Mycophenolate Mofetil, discontinuing Tacrolimus once Everolimus level within goal range OR randomized to continued maintenance with Tacrolimus plus Mycophenolate Mofetil.
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver
      transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the
      nephrotoxicity side effects of Tacrolimus. Replacement of Tacrolimus by Everolimus may have a
      reduced incidence of renal dysfunction in liver transplant patients who already have chronic
      kidney disease or peri-operative acute kidney injury. Liver transplant patients receive
      potent induction immunosuppression in the form of rabbit anti thymocyte globulin.
      Investigators believe that in conjunction with this induction regimen, patients can be
      maintained on Everolimus monotherapy without the risk of rejection. Additionally, Everolimus
      is known to induce tolerance in transplant recipients. Tolerant patients do not require
      immunosuppression to accept transplant organs. Tacrolimus is a widely used in liver
      transplant recipients for immunosuppression, however it is associated with nephrotoxicity.
      Everolimus, on the other hand lacks nephrotoxicity. Whether replacement of tacrolimus by
      Everolimus preserves kidney function in patients with pre-existing chronic kidney disease or
      acute kidney injury is not well established. Also, the efficacy and safety of reduced-dose
      Everolimus with or without Mycophenolate Mofetil in prevention of rejection is unknown.

      Primary Aim Assess the effect of Everolimus with or without Mycophenolate Mofetil versus
      Tacrolimus plus Mycophenolate Mofetil therapy on renal function measured by Glomerular
      Filtration Rate (GFR). Secondary Aims

      Compare the efficacy of Everolimus plus Mycophenolate Mofetil versus Tacrolimus plus
      Mycophenolate Mofetil therapy as measured by the following:

        -  Biopsy-confirmed acute rejection

        -  Hyperlipidemia

        -  Proteinuria

        -  % regulatory T-cells in circulation

        -  NODAT [New Onset Diabetes mellitus After Transplant], hypertension and malignancy

        -  Tolerance measured by gene profiling at year 1, 2 and 3
    

Eligibility criteria:

        Inclusion Criteria:

          -  Liver transplant recipients ≥ 18 years old

          -  Baseline renal dysfunction (GFR ≤ 60 mL/min)

          -  Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 3 - 5 mg/kg)

          -  Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis

        Exclusion Criteria:

          -  Increased risk of rejection: autoimmune hepatitis, primary biliary cirrhosis, primary
             sclerosing cholangitis, positive crossmatch, retransplantation

          -  Incompletely healed incision or other wound healing issues at time of randomization

          -  Multiple or previous organ transplantation

          -  Severe, uncontrolled hypercholesterolemia (> 9mmol/L) or hypertriglyceridemia (>8.5
             mmol/L) in the 6 mo prior to transplantation

          -  Insurance company unwilling to pay for the cost of the everolimus

          -  Pregnant women

          -  Unable to provide informed consent