Kidney Transplant
Conditions
Keywords
Kidney transplant
Brief 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
Detailed description
We 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. We will then compare biopsy derived measures of allograft fibrosis (CADI, Sirius Red, Banff Chronicity Index) and GFR in the two groups
Interventions
DRUGSirolimus
Tacrolimus to Sirolimus
DRUGTacrolimus
dosage per trough level
Sponsors
Pfizer
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biopsy-derived Measures of Fibrosis | 12 months | The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in iGFR | 12 months | We will also compare the change in iGFR (as well as estimated GFR) from time of conversion to 12 and 24 months of follow up by paired t-test between groups. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus patients will be switched from Tacrolimus to Sirolimus
Sirolumus: Tacrolimus to Sirolimus
Tacrolimus: dosage per trough level | 7 |
| Tacrolimus Patient will stay on Tacrolimus | 5 |
| Total | 12 |
Baseline characteristics
| Characteristic | Sirolimus | Tacrolimus | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 5 Participants | 11 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 0 / 5 |
| serious Total, serious adverse events | 2 / 7 | 0 / 5 |
Outcome results
Primary
Biopsy-derived Measures of Fibrosis
The primary analyses will compare biopsy-derived measures of fibrosis in the Tac-maintenance and SRL groups using the t-test.
Time frame: 12 months
Population: Early termination; Sponsor discontinued the study for corporate reasons. No data analyzed. Data were not collected and the outcome measure was not analyzed.
Secondary
Change in iGFR
We will also compare the change in iGFR (as well as estimated GFR) from time of conversion to 12 and 24 months of follow up by paired t-test between groups.
Time frame: 12 months
Population: Early termination; Sponsor discontinued the study for corporate reasons. No data analyzed. Data were not collected and the outcome measure was not analyzed.