Everolimus Plus Mycophenolic Acid for Kidney Preservation in Liver Transplant Recipients With Impaired Kidney Function
Everolimus Plus Mycophenolic Acid for Kidney Preservation in Liver Transplant Recipients With Impaired Kidney Function
Tacrolimus is the standard immunosuppressive drug used to prevent organ rejection post liver
 transplant. One side effect of Tacrolimus is nephrotoxicity. Everolimus does not have the
 nephrotoxicity side effects of Tacrolimus. Replacement of Tacrolimus by Everolimus may have a
 reduced incidence of renal dysfunction in liver transplant patients who already have chronic
 kidney disease or peri-operative acute kidney injury. Liver transplant patients receive
 potent induction immunosuppression in the form of rabbit anti thymocyte globulin.
 Investigators believe that in conjunction with this induction regimen, patients can be
 maintained on Everolimus monotherapy without the risk of rejection. Additionally, Everolimus
 is known to induce tolerance in transplant recipients. Tolerant patients do not require
 immunosuppression to accept transplant organs. Tacrolimus is a widely used in liver
 transplant recipients for immunosuppression, however it is associated with nephrotoxicity.
 Everolimus, on the other hand lacks nephrotoxicity. Whether replacement of tacrolimus by
 Everolimus preserves kidney function in patients with pre-existing chronic kidney disease or
 acute kidney injury is not well established. Also, the efficacy and safety of reduced-dose
 Everolimus with or without Mycophenolate Mofetil in prevention of rejection is unknown.

 Primary Aim Assess the effect of Everolimus with or without Mycophenolate Mofetil versus
 Tacrolimus plus Mycophenolate Mofetil therapy on renal function measured by Glomerular
 Filtration Rate (GFR). Secondary Aims

 Compare the efficacy of Everolimus plus Mycophenolate Mofetil versus Tacrolimus plus
 Mycophenolate Mofetil therapy as measured by the following:

 -  Biopsy-confirmed acute rejection

 -  Hyperlipidemia

 -  Proteinuria

 -  % regulatory T-cells in circulation

 -  NODAT [New Onset Diabetes mellitus After Transplant], hypertension and malignancy

 -  Tolerance measured by gene profiling at year 1, 2 and 3
Following transplant, prior to the one month post transplant visit, subjects will be
 approached either in the transplant unit in the hospital or at the transplant clinic in the
 hospital for study participation. Following enrollment, subjects will be randomized at one
 month post transplant to reduced dose Tacrolimus plus Mycophenolate Mofetil immunosuppression
 (control group) or to Everolimus plus Mycophenolate Mofetil (study group) maintenance
 immunosuppression.

 After liver transplant, all patients will receive the standard induction regimen and
 Tacrolimus monotherapy.

 INDUCTION:

 Rabbit anti-thymocyte globulin (rATG) 1.5 mg/kg of actual body weight rounded to nearest 25
 mg and capped at 150 mg for up to three doses given IV on post-operative day (POD) 1, 3, and
 5. Some patients may receive only one dose if considered too frail to need all three doses.

 30 minutes prior to infusion, pre-medicate with the following: Daily steroid dose
 Acetaminophen (Tylenol®) 650 mg PO or per NG x 1 dose B - Lay Summary & Research Design
 Diphenhydramine (Benadryl®) 25 mg IV push x 1 dose

 Steroids:

 Methylprednisolone (Solu-Medrol®) 250 mg IV push x 1 dose on POD 1 (given 30 minutes prior to
 rATG) and 125 mg IV push x 1 dose on POD 3.

 Maintenance:

 Low dose Tacrolimus (FK / Prograf®) (titrated to a goal trough of 6 ± 1 ng/mL) plus
 Mycophenolate Mofetil 500 mg BID.

 RANDOMIZATION:

 On POD 30, patients meeting study criteria will be randomized to either the study arm or
 control arm. Patients randomized to the study arm will be converted to Everolimus (target
 trough levels 4-8 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. The control arm will
 be maintained on the low dose Tacrolimus plus Mycophenolate Mofetil therapy.

 At 3 months, patients with GFR <=60 will proceed to reduced dose Everolimus (target trough
 levels 3-6 ng/mL) plus Mycophenolate Mofetil 500 mg BID therapy. Patients with GFR >60 will
 proceed to Everolimus monotherapy (target trough levels 4-8 ng/mL).

 Complete blood counts, liver function panels, and drug levels will be monitored per Standard
 of Care [SOC]: initially twice per week for first month, once per week for next two months,
 once every other week for next three weeks, and then once monthly. Ultrasound, ERCP, biopsy
 as needed by clinical situation as SOC.
Inclusion Criteria:

 -  Liver transplant recipients ≥ 18 years old

 -  Baseline renal dysfunction (GFR ≤ 60 mL/min)

 -  Rabbit anti-thymocyte globulin (rATG) induction (cumulative dose 3 - 5 mg/kg)

 -  Indication for transplant: ethanol, hepatitis C, or nonalcoholic steatohepatitis

 Exclusion Criteria:

 -  Increased risk of rejection: autoimmune hepatitis, primary biliary cirrhosis, primary
 sclerosing cholangitis, positive crossmatch, retransplantation

 -  Incompletely healed incision or other wound healing issues at time of randomization

 -  Multiple or previous organ transplantation

 -  Severe, uncontrolled hypercholesterolemia (> 9mmol/L) or hypertriglyceridemia (>8.5
 mmol/L) in the 6 mo prior to transplantation

 -  Insurance company unwilling to pay for the cost of the everolimus

 -  Pregnant women

 -  Unable to provide informed consent