Randomized Conversion of Calcineurin-Inhibitors in Renal Allograft Recipients

• Evaluate whether CI conversion (tacrolimus→sirolimus) contributes positively or negatively on the renal allograft function calculated with e-GFR and proteinuria [ Time Frame: 6 Months, 12 Months, and 24 Months ] [ Designated as safety issue: Yes ]
  Previous chart reviews indicated a prednisone-free regiment (treatment) conversion from calcineurin inhibitors to sirolimus at 1 yr post-transplant did not show an increase in risk for acute rejection or graft loss. A trend towards a better Glomerular filtration rate (GFR) was noted after conversion from calcineurin inhibitors to sirolimus.
• Evaluate if CI conversion impacts on lipid profile, incidence of hypertension, malignancies, and opportunistic infections and post-transplant DM [ Time Frame: 6 Months, 12 Months, 24 Months ] [ Designated as safety issue: Yes ]
  In addition to monitoring renal allograft function, evaluation will be conducted on the incidence of acute rejection, patient and graft survival, the impact of CI conversion on the lipid profile, the incidence of hypertension, malignancies, opportunistic infections and post-transplant DM (de novo diabetes mellitus).
• Patient and graft survival [ Time Frame: 6 Months, 12 Months, 24 Months ] [ Designated as safety issue: Yes ]
  This study also reviews the impact of the immunosuppressive medications on patient and graft survival.
• Evaluate possible modifications of lymphocytes function before and after conversion (tacrolimus→sirolimus) [ Time Frame: Baseline pre-randomization labs, at 6, 12 and 24 Months ] [ Designated as safety issue: Yes ]
  With peripheral leukocytes taken at baseline (first visit) prior to randomization and at 6, 12 and 24 Months post-randomization, researchers will also review possible modifications of lymphocytes function and of the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus (randomization).
• Assess tubular toxicity by evaluating urinary biomarkers [ Time Frame: 6 Months, 12 Months, 24 Months ] [ Designated as safety issue: Yes ]
  Urine will be collected to assess tubular toxicity by evaluating urinary biomarkers.

• Evaluate whether CI conversion (tacrolimus→sirolimus) contributes positively or negatively on the renal allograft function calculated with e-GFR and proteinuria.
• Patient and graft survival
• Evaluate if CI conversion impacts on lipid profile

This study is being done to investigate the impact of changing immunosuppressive medications from tacrolimus (Prograf®) to sirolimus (Rapamune®) between 6 and 24 months post transplant. The primary purpose of this research study is to evaluate whether the use of mycophenolate mofetil(MMF)/Cellcept® and tacrolimus(TAC)/Prograf® (Group 1) or mycophenolate mofetil(MMF)/Cellcept® and sirolimus/Rapamune® (Group 2) impacts the incidence of acute cellular rejection in post kidney transplant patients. This study will examine whether switching from tacrolimus to sirolimus will better preserve long-term kidney function.

For this research study, between 6 and 24 Months post-transplant, we plan to prospectively randomize 2:1 renal transplant patients to either:

• Substitute tacrolimus (TAC) with sirolimus and continue mycophenolate mofetil (MMF) or
• Continue with tacrolimus (TAC) and mycophenolate mofetil (MMF)

A total of 400 patients are expected to be screened for the randomization. We expect to randomize 275 renal transplant patients into this protocol (275 donors to be recruited).

The following data will be collected at the time of randomization:

Recipient demographics: (i) age at transplantation, (ii) sex, and (iii) race.

Clinical history: (i) causes of end-stage renal disease, and (ii) past medical history.

Transplant related information: (i) donor age, (ii) cadaveric versus living kidney transplant, (iii) histocompatibility and cross match data, (iv) viral serology, (v) history of acute rejection and delayed graft function, (vi) use of induction therapy and immunosuppressants, (vii) use of ACEI and/or ARB, and (viii) level of renal allograft function-estimated GFR (e-GFR(12) using MDRD formula, proteinuria.

Peripheral blood leukocytes will be obtained from renal transplant recipients for baseline (prior to randomization) lymphocytes functional activity and characterization of lymphocytes subpopulations by flow cytometry analysis.

Peripheral donor leukocytes (from living donor patients) will also be obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function.

The recipients assigned to continue with tacrolimus and MMF will be routinely followed at the outpatient Comprehensive Transplant Center (CTC) with monthly labs. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity and to characterize lymphocytes subpopulations by flow cytometry analysis.

Post randomization: The recipients assigned to switch from tacrolimus to sirolimus and continue with MMF will be routinely followed at the CTC with monthly labs. During the period of conversion from tacrolimus to sirolimus, weekly labs will be obtained to monitor renal function and bone marrow function. In addition to labs at baseline pre-randomization, 6, 12 and 24 Months post-randomization, peripheral blood leukocytes will be obtained to study lymphocytes functional activity to characterize lymphocytes subpopulations by flow cytometry analysis. Urine will be collected to assess tubular toxicity by evaluating urinary biomarkers.

Both groups of patients will be followed for 2 years post-randomization. In addition to monitoring renal allograft function, we will evaluate the incidence of acute rejection, patient and graft survival, impact of CI conversion on the lipid profile, incidence of hypertension, malignancies, opportunistic infections, and post-transplant DM. For those willing to undergo an optional kidney biopsy, one will be performed at the end of the second year in order to evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups.

With the peripheral leukocytes obtained at baseline prior to randomization and at 6, 12 and 24 Months post-randomization, we will investigate possible modifications of lymphocytes function and the lymphocytes subpopulations that might have occurred as a consequence of the switch from tacrolimus to sirolimus.

Obtaining renal allograft tissue samples at 24 months post randomization can have potential important ramifications to help explain the mechanisms of fibrosis and tubular atrophy typically associated with CI and the role of CI elimination with the substitution of SRL. All data will then be analyzed comparing gene expression profiles of peripheral blood (Paxgene tubes are routinely collected at the different time points as part of the original study). Based on power analysis, we will perform 24 months post randomization biopsies in 70% of the total subjects enrolled in the study (approximately 46 subjects from the tacrolimus/MMF group and approximately 93 subjects from the sirolimus/MMF group).

We plan to obtain renal allograft biopsies at 24 Months for those that consent for this additional biopsy. This will be compared to the standard of care 12 months post-transplant biopsy to allow us to address the effect of immunosuppressive modifications on renal allograft pathology at 24 months post randomization. Renal allograft biopsies will also be stored in RNA later to further extend our knowledge on the effect of CI free immunosuppression on gene expression profiles.

• Drug: Sirolimus
  Sirolimus will initially be given at a dose of 2-4 mg orally (PO) daily. The dose will be modified to achieve 24 hours trough concentrations of 6-10 ng/ml by HPLC assay. This medication will be given in an open label fashion. The first dose of sirolimus will be given at the time of randomization to those patients assigned to have tacrolimus switched to sirolimus.
  Other Name: Rapamune
• Other: Demographic Data, Medical History, and Donor Data
  Age at transplant, sex, race, cause of end-stage renal disease, medical history, donor age, cadaveric vs. living kidney transplant, histocompatibility/cross match data, viral serology, history of acute rejection and delayed graft function, use of induction therapy and immunosuppressants, use of ACEI and/or ARB level of renal allograft function-estimated GFR (e-GFR(12) using MDRD formula, proteinuria.
• Procedure: Blood Draws for Control Group
  Subjects maintaining standard of care drug treatment of TAC and MMF will have monthly labs in addition to the baseline pre-randomization labs, at 6, 12, and 24 Months post-randomization. Peripheral blood leukocytes will be obtained.
• Procedure: Blood Draws for Experimental Group
  This group will have monthly labs taken but will also have weekly labs during the period of conversion to monitor renal function and bone marrow function. In addition to the baseline pre-randomization labs, and labs collected at 6, 12, and 24 Months post-randomization, peripheral blood leukocytes will be obtained.
• Procedure: Donor Blood Draws
  Peripheral blood leukocytes from living donors obtained at the time of randomization. These donor leukocytes will be used as stimulator cells to study the functional activity of the recipient's lymphocytes function.
• Other: Donor Information
  Donor age, cadaveric vs. living donor, and histocompatibility and cross match to recipient
• Procedure: Kidney Biopsy
  Kidney biopsy at 24 Months to compare to the standard of care biopsy taken at 12 Months. This information will help evaluate renal allograft pathology and renal allograft tissue gene expression profiles of the two groups. Renal allograft biopsies will be stored in RNA later (preservative) to further extend knowledge on the effect of CI free immunosuppression on gene expression profiles.

• Active Comparator: Control
  Group 1 will continue immunosuppression medication per standard of care (SOC) at Northwestern by taking mycophenolate mofetil and tacrolimus.
  Interventions:

  • Other: Demographic Data, Medical History, and Donor Data
  • Procedure: Blood Draws for Control Group
  • Procedure: Kidney Biopsy
• Experimental: Transition to Sirolimus Group
  Group 2 will switch immunosuppression medication to taking mycophenolate mofetil and sirolimus
  Interventions:

  • Drug: Sirolimus
  • Other: Demographic Data, Medical History, and Donor Data
  • Procedure: Blood Draws for Experimental Group
  • Procedure: Kidney Biopsy
• Donors
  Data and blood samples from the donors are collected in this study to contribute to the general knowledge to be used in assessing the two donor recipient groups, which are the target of this study.
  Interventions:

  • Procedure: Donor Blood Draws
  • Other: Donor Information

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Inclusion Criteria:

1. Subjects should be adults ≥ 18- ≤ 70 years of age
2. Subjects can be either gender or of any ethnic background
3. Subjects should be single organ recipients (kidney only)
4. Subjects must be able to understand the protocol and provide informed consent.

Exclusion Criteria:

1. Subjects with ESRD secondary to primary FSGS (focal segmental glomerulonephritis).
2. Inability to comply with study procedures
3. Inability to sign the informed consent
4. Subjects with a significant or active infection
5. Subjects who are pregnant or nursing females
6. Subjects with a history of severe hyperlipidemia not controlled with statins, patients with at total cholesterol of > 400 mg/dl
7. Subjects with a platelet count <100,000mm3 WBC< 2,000mm3
8. Subjects with severe proteinuria at the time of randomization (>2gm/day)
9. Subjects with more then 2 episodes of acute cellular rejection post transplantation will be excluded from this study
10. An estimated GFR<40 cc/min
11. A history of malignancy during the post-transplant period (other than treated basal cell cancer and/or squamous cell cancer)
12. Subjects, who, due to the existence of a surgical, medical or psychiatric condition, other than the current transplant, which in the opinion of the investigator, precludes enrollment into this trial
13. A history of ACR during the most recent previous 3 months prior to randomization