Brief Summary
The purpose of this study is to find out how well the current drug regimen (including low Prograf dose and Myfortic, which is usually recommended to prevent any further deterioration in the kidney function) works and how safe it is when compared to a combination of Zortress and Myfortic in patients with chronic kidney injury associated with Prograf or Neoral use.
Brief Title
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
Detailed Description
Specific Aim 1: To investigate allograft and peripheral blood cell gene expression patterns of patients with CAI by using Affymetrix microarrays.
Hypothesis 1: Gene expression patterns of patients with biopsy findings suggesting calcineurin inhibitor (CNI) toxicity without significant tubulointerstitial infiltrates or transplant glomerulopathy might demonstrate upregulation of genes related to tissue injury, fibrosis, and extracellular matrix deposition without upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines comparing to patients with significant tubulointerstitial infiltrates and/or transplant glomerulopathy that might show upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines.
Specific Aim 2: The effect of everolimus (Zortress)/ mycophenolate sodium (EC-MPS, myfortic®) treatment on allograft and peripheral gene expression patterns.
Hypothesis 2: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) treatment attenuates the progression of CAI due to CNI toxicity by downregulating the expression of genes related to fibrosis, such as, transforming growth factor-β, thrombospondin 1, and platelet derived growth factor-C.
Specific Aim 3: To document the clinical outcomes of everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) in patients with CAI due to CNI toxicity Hypothesis 3: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) can attenuate the progression of CAI due to CNI toxicity and may improve the creatinine clearance.
Hypothesis 1: Gene expression patterns of patients with biopsy findings suggesting calcineurin inhibitor (CNI) toxicity without significant tubulointerstitial infiltrates or transplant glomerulopathy might demonstrate upregulation of genes related to tissue injury, fibrosis, and extracellular matrix deposition without upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines comparing to patients with significant tubulointerstitial infiltrates and/or transplant glomerulopathy that might show upregulation of genes related to alloimmune response, such as, T and/or B lymphocyte activation markers, surface receptors, co-stimulation molecules, adhesion molecules, cytokines, and chemokines.
Specific Aim 2: The effect of everolimus (Zortress)/ mycophenolate sodium (EC-MPS, myfortic®) treatment on allograft and peripheral gene expression patterns.
Hypothesis 2: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) treatment attenuates the progression of CAI due to CNI toxicity by downregulating the expression of genes related to fibrosis, such as, transforming growth factor-β, thrombospondin 1, and platelet derived growth factor-C.
Specific Aim 3: To document the clinical outcomes of everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) in patients with CAI due to CNI toxicity Hypothesis 3: Everolimus (Zortress) and mycophenolate sodium (EC-MPS, myfortic®) can attenuate the progression of CAI due to CNI toxicity and may improve the creatinine clearance.
Completion Date
Completion Date Type
Actual
Conditions
Chronic Allograft Injury
Calcineurin Inhibitor Toxicity
Eligibility Criteria
Inclusion Criteria:
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
Exclusion Criteria:
1. 24 hour urine protein or spot urine protein/creatinine ratio \> 500 mg/day
2. Estimated glomerular filtration rate (eGFR) \< 30 ml/min by modification of Diet in Renal Disease( MDRD) or 24 hour urine collection
3. Patients with Donor-specific antibody (DSA) by Luminex (mean fluorescence intensity values \> 1,000)
4. Recipients of multiple organ transplants or ABO-incompatible allograft
5. Current panel reactive antibody (PRA) greater than 30 percent
6. Graft loss at randomization
7. Pregnant women
8. Previous history of acute rejection
9. Previous history of allergy or intolerance to Zortress or Myfortic
10. Platelet count less than 100,000
11. White Blood Cell (WBC) less than 3,000
12. Hb less than 9 g/dL or Htc less than 30%
13. Biopsy findings of
* Chronic antibody mediated rejection
* Acute rejection
* Positive C4d staining
* Interstitial infiltrates more than 25% of the area
* Transplant glomerulopathy
* Recurrent or de novo glomerular disease
* Polyoma nephropathy or positive simian virus 40 (SV40) staining
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
Exclusion Criteria:
1. 24 hour urine protein or spot urine protein/creatinine ratio \> 500 mg/day
2. Estimated glomerular filtration rate (eGFR) \< 30 ml/min by modification of Diet in Renal Disease( MDRD) or 24 hour urine collection
3. Patients with Donor-specific antibody (DSA) by Luminex (mean fluorescence intensity values \> 1,000)
4. Recipients of multiple organ transplants or ABO-incompatible allograft
5. Current panel reactive antibody (PRA) greater than 30 percent
6. Graft loss at randomization
7. Pregnant women
8. Previous history of acute rejection
9. Previous history of allergy or intolerance to Zortress or Myfortic
10. Platelet count less than 100,000
11. White Blood Cell (WBC) less than 3,000
12. Hb less than 9 g/dL or Htc less than 30%
13. Biopsy findings of
* Chronic antibody mediated rejection
* Acute rejection
* Positive C4d staining
* Interstitial infiltrates more than 25% of the area
* Transplant glomerulopathy
* Recurrent or de novo glomerular disease
* Polyoma nephropathy or positive simian virus 40 (SV40) staining
Inclusion Criteria
Inclusion Criteria:
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
All patients with biopsy proven pure chronic allograft injury due to CNI toxicity.
Gender
All
Gender Based
false
Keywords
CNI toxicity
CAI
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
NCT Id
NCT01473732
Org Class
Other
Org Full Name
Montefiore Medical Center
Org Study Id
11-05-196
Overall Status
Terminated
Phases
Not Applicable
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity
Primary Outcomes
Outcome Description
Estimated glomerular filtration rate (eGFR) indicates kidney function. Normal eGFR value for healthy is 80-120ml/min. For transplants, it is expected to be 60-80 ml/min.
Outcome Measure
Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test
Outcome Time Frame
Baseline, One year
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Enver Akalin
Investigator Email
eakalin@montefiore.org
Investigator Phone
718-920-4815