Study in Recipients of Renal Transplant Allograft to Evaluate the Impact of Two Immunosuppressive Regimens
Condition: End Stage Renal Failure With Renal Transplant
MeSH terms: Kidney Failure, Chronic
Study type: Interventional

Summary: 
      The immune system is the body's defense against infection and other disease. After
      transplantation, the body sees the new organ as "foreign" and tries to destroy or "reject"
      it. Immunosuppressive medications help to prevent the immune system from attacking a
      transplanted organ. The primary purpose of this study is to investigate the impact of two
      maintenance immunosuppressive regimens. Subjects who enroll in this study will be randomly
      selected to have tacrolimus and everolimus (group 1) or tacrolimus and mycophenolate mofetil
      (group 2) as their immunosuppression medication.

      This study will enroll adult patients who are scheduled to receive a kidney transplant.

      The study is designed to understand the mechanisms of Everolimus in regards to kidney
      function in transplant recipients. The investigators hypothesis is that decreased exposure to
      Tacrolimus to the immune system will then translate in better renal allograft function.
    

Detailed description: 
      Immunosuppressive therapy with the calcineurin inhibitors (CNI) Cyclosporine (CsA) and
      Tacrolimus (Tac), have radically changed the field of organ transplantation. Ironically,
      although extensively and effectively used for kidney transplantation and other solid organ
      transplants, CsA and Tac cause important adverse renal side effects: acute and chronic renal
      dysfunction, hemolytic-uremic syndrome, hypertension, electrolyte disturbances and tubular
      acidosis. Chronic nephrotoxicity from CNI has been implicated as a principal cause of
      post-transplant renal dysfunction and it is characterized by an irreversible and progressive
      tubular atrophy, interstitial fibrosis, and focal hyalinosis of small renal arteries and
      arterioles. Furthermore, this class of medications is associated also, by blocking
      Interleukin-2 (IL2) production, with negative impact on regulatory T cells (T-Regs)
      generation (an important subpopulation of T helper cells that has been associated with
      positive immunomodulation and donor specific hypo responsiveness).

      In renal transplant recipients, complete avoidance of calcineurin inhibitors from the time of
      renal transplant surgery has been associated with increased incidence of acute cellular
      rejection, and the combination of mammalian target of rapamycin (mTOR) inhibitors with full
      dose CNI has been shown to be synergistically nephrotoxic and it has been associated with
      poor graft outcome. CNI conversion to mTOR inhibitors, at different time point
      post-transplant, has been tested with promising results, by different investigators and by
      the investigators group. The investigators have shown that in a Prednisone-free
      immunosuppression, conversion from Tacrolimus to mTor inhibitors at different time point post
      transplant is safe, it is not associated with an increased risk of acute rejection and more
      importantly it is associated with an a persistent increase of regulatory T cells (Data
      presented at the American Transplant Congress (ATC) 09 and 2010) Recently the A2309 study
      allowed Everolimus to be FDA approved. The A2309 was a study designed to combined reduced
      dose Cyclosporine+Everolimus. Interesting the reduced exposure to Cyclosporine was not
      associated with an increase rate of albumin-creatinine ratio (ACR) and renal allograft
      function was well maintained compared to the control group. The A2309 opens then an important
      question regarding the mechanism(s) that can explain the efficacy of a low dose CNI with an
      mTOR inhibitor in preventing acute allograft rejection.

      The present proposal is designed to understand the mechanisms of the synergistic effect(s) of
      low dose CNI and mTOR inhibitors (Everolimus) in controlling allo-reactive T and B cells
      while expanding T-Regs.

      The investigators hypothesis based in published data and from their laboratory (see
      preliminary data-Supportive documents), is that mTOR inhibitors allow expansion of T-Regs and
      low exposure of CNI is sufficient to control allo-reactive T cells. Decrease exposure to CNI
      and concomitant increase of T-Regs will then translate in better renal allograft function and
      histology.
    

Intervention name(s): Tacrolimus with MMF; Group 2: Tacrolimus with Everolimus.
Intervention type(s): Drug; Drug
Intervention description(s): Standard dose Tacrolimus and MMF. This will follow standard of care procedures at Northwestern Memorial Hospital's Comprehensive Transplant Center. MMF trough or area under the concentration time curve (AUC) shall not be used to adjust dosing. In this group, Tacrolimus will be initiated according to our practice. The Tacrolimus dose will be adjusted from day 3 on to achieve a target whole blood trough concentration of 8 ng/mL to 10 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be reduced to 6 ng/mL to 8 ng/mL. After month 6, the target level of Tacrolimus will be reduced to 4 ng/mL to 8 ng/mL.; From day 5 on, the starting dose of Everolimus (0.75 mg bid) will be increased if the trough level is < 3 ng/mL, or reduced if the trough level is > 8 ng/mL. Tacrolimus will be initiated according to our practice. In this treatment arm, the Tacrolimus dose will be adjusted from day 3 on, to a target whole blood trough concentration of 4 ng/mL to 7 ng/mL. From month 2 until Month 6, the target Tacrolimus trough level will be 3 ng/mL to 6 ng/mL. After month 6, the Tacrolimus dose should be adjusted in order to achieve a target trough level of 2 ng/mL to 5 ng/mL. MMF dose will be initiated as 1 g b.i.d. (2 g/day). Adjustments should be made for adverse events including but not limited to gastrointestinal intolerance and a decrease in white blood cell (WBC).
Other intervention name(s): Tacrolimus; FK 506; mycophenolate mofetil; MMF; Everolimus; Zortress; Tacrolimus; FK 506
Intervention MeSH terms: Mycophenolic Acid; Everolimus; Tacrolimus
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: transplant; kidney; renal disease