The Vienna Prograf and Endothelial Progenitor Cell Study
Condition: End Stage Renal Disease
MeSH terms: Kidney Failure, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      The aim of the study is to determine if the conversion from the immunosuppressive agent
      cyclosporine to tacrolimus contributes to an improvement of the cardiovascular risk factors,
      better kidney function and immune system.
    

Detailed description: 
      In addition to hypertension, diabetes, hyperlipidemia and smoking, as well as other
      non-traditional risk factors such as elevated C-reactive protein, homocysteine, Lp(a), or
      reduced renal function, depletion of endothelial progenitor cells (EPC) in the peripheral
      circulation may represent another important explanation for the excess cardiovascular
      morbidity of kidney transplant recipients. In this context, the potential association of
      immunosuppressive therapy with EPCs in kidney transplant recipients deserves special
      consideration. The use of tacrolimus associated with a more favorable cardiovascular risk
      factors profile in terms of improved blood pressure and lipid levels in kidney transplant
      recipients compared to cyclosporine users. Therefore, one can speculate whether tacrolimus
      users might have greater EPC counts compared to patients treated with cyclosporine.

      In a pilot study we cross-sectionally studied EPC counts in 90 stable, middle-aged kidney
      transplant recipients. From multivariate analyses, we found a independent inverse association
      between EPC counts and body mass index and systolic blood pressure. Statin use was associated
      with greater EPC counts, while patients receiving azathioprine had lower EPC counts. These
      findings raised the hypothesis whether EPCs are responsible, at least in part, for the
      well-established association between these factors and cardiovascular outcomes.

      Cystatin C is superior to serum creatinine as a marker of kidney function since cystatin C is
      a more sensitive marker than serum creatine for small changes in glomerular filtration rate.
      Until now, there are no available data on the change of cystatin C as a measure of graft
      function after conversion of a cyclosporine based immunosuppressive regimen to tacrolimus.

      There is accumulating evidence for an important pathogenetic role of donor-reactive
      antibodies in kidney allograft rejection. Recent studies suggest an anti-humoral activity of
      tacrolimus in the setting of chronic rejection. Recent findings suggest that in patients who
      are on cyclosporine, tacrolimus rescue therapy could efficiently inhibit antibody formation.

      Objective 1: To evaluate the change in endothelial progenitor cell (EPC) count in kidney
      graft recipients converted from cyclosporine to tacrolimus.

      Objective 2: To evaluate the change in cystatin C as a measure of renal function in kidney
      graft recipients converted from cyclosporine to tacrolimus.

      Objective 3: To determine the effect of tacrolimus on humoral alloreactivity in kidney graft
      recipients Study design: A 2:1 randomized, parallel group, open-label, prospective trial
      comparing two different immunosuppressive regimens in approximately 148 patients. Group A:
      Convert to tacrolimus in combination with/without mycophenolate mofetil and/or steroids.
      Group B: Maintain cyclosporine in combination with/without mycophenolate mofetil and/or
      steroids. Patients will be followed up for 24 months after conversion.

      In an amendment (August 2006) we registered pharmacogenetic analyses of the multi-drug
      resistance transporter 1 (MDR1) gene (gene symbol: ABCB1). The patients´ DNA is extracted
      from peripheral venous blood manually with industrial extraction kits. Two gene sections are
      amplified by polymerase chain reaction (PCR). Mutations are determined by restriction enzymes
      (restriction fragment length polymorphisms, RFLP).
    

Intervention name(s): Ciclosporin; Tacrolimus
Intervention type(s): Drug; Drug
Intervention description(s): Maintain ciclosporin in combination with/without mycophenolate mofetil and with/without steroids at target trough levels of 70-150ng/mL.; Conversion from ciclosporin to tacrolimus at target trough levels of 5-8 ng/mL in combination with/without mycophenolate mofetil and with/without steroids.
Other intervention name(s): Sandimmun Neoral; Prograf
Intervention MeSH terms: Cyclosporine; Tacrolimus; Cyclosporins
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: kidney; transplantation; tacrolimus; cyclosporine; conversion