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

Montefiore Medicine Academic Health System

Status

Terminated

Conditions

Calcineurin Inhibitor Toxicity

Chronic Allograft Injury

Treatments

Drug: Tacrolimus

Drug: Mycophenolic acid

Drug: Everolimus

Study type

Interventional

Funder types

Other

Identifiers

NCT01473732

11-05-196

Details and patient eligibility

About

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.

Full 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.

Enrollment

2 patients

Sex

All

Volunteers

No Healthy Volunteers

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