Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity

Study Overview
=================
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.

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.

Official Title
-----------------
Mechanisms and Treatment of Chronic Allograft Injury (CAI) Due to Calcineurin Inhibitor (CNI) Toxicity

Conditions
-----------------
Calcineurin Inhibitor Toxicity, Chronic Allograft Injury

Intervention / Treatment
-----------------
* Drug: Everolimus
* Drug: Tacrolimus
* Drug: Mycophenolic acid


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: All patients with biopsy proven pure chronic allograft injury due to CNI toxicity. Exclusion Criteria: 24 hour urine protein or spot urine protein/creatinine ratio > 500 mg/day Estimated glomerular filtration rate (eGFR) < 30 ml/min by modification of Diet in Renal Disease( MDRD) or 24 hour urine collection Patients with Donor-specific antibody (DSA) by Luminex (mean fluorescence intensity values > 1,000) Recipients of multiple organ transplants or ABO-incompatible allograft Current panel reactive antibody (PRA) greater than 30 percent Graft loss at randomization Pregnant women Previous history of acute rejection Previous history of allergy or intolerance to Zortress or Myfortic Platelet count less than 100,000 White Blood Cell (WBC) less than 3,000 Hb less than 9 g/dL or Htc less than 30% 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
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus (Zortress)<br> | Drug: Everolimus<br>* Starting dose 1.5 mg bid, target trough level 6-10 ng/ml.<br>* Other names: Zortress;Drug: Mycophenolic acid<br>* Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.<br>* Other names: Myfortic;|
| Active Comparator: Reduced dose Tacrolimus (Prograf)<br> | Drug: Tacrolimus<br>* Target trough level of Tacrolimus 3-5 ng/ml.<br>* Other names: Prograf;Drug: Mycophenolic acid<br>* Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Used in both arms. Used for one year.<br>* Other names: Myfortic;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in eGFR (Creatinine Clearance) as Measured by Serum Creatinine Blood Test | 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. | Baseline, One year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CNI toxicity, CAI