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

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.

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