Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression-
| Status: | Completed |
|---|---|
| Conditions: | Renal Impairment / Chronic Kidney Disease |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/2/2016 |
| Start Date: | July 2010 |
| End Date: | December 2014 |
| Contact: | Titte Srinvas, MD |
| Phone: | 216 445 0034 |
Renal Allograft Function and Histology Following Switching From A Tacrolimus to Sirolimus (SRL)-Based Immunosuppression- Clinical and Mechanistic Impact
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
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
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
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
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
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