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

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.

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.

• Chronic Allograft Injury
• Calcineurin Inhibitor Toxicity

• Drug: Everolimus
  Starting dose 1.5 mg bid, target trough level 6-10 ng/ml. Myfortic Min. dose 360 mg bid and Max dose 720 mg bid. Both for one year.
• Drug: Tacrolimus
  Target trough level of Tacrolimus 3-5 ng/ml. Myfortic Min. 360 mg bid and Max. 720 mg bid Both for one year.

• Experimental: Everolimus (Zortress)+ Mycophenolic acid(Myfortic)
  Intervention: Drug: Everolimus
• Active Comparator: Reduced dose Prograf+ Mycophenolic acid(Myfortic)
  Intervention: Drug: Tacrolimus

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. eGFR < 30 ml/min by MDRD or 24 hour urine collection
3. Patients with DSAs by Luminex (mean fluorescence intensity values > 1,000)
4. Recipients of multiple organ transplants or ABO-incompatible allograft
5. Current 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. 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 SV40 staining