Pediatric Kidney Transplant Study of Sirolimus, Mycophenolate Mofetil, and Corticosteroids vs Calcineurin Inhibitor Based Immunosuppression

Advances in immunosuppressive therapies in pediatrics have been associated with rapidly
falling incidence of acute rejection and improving allograft survival. In recent analyses
of the NAPRTCS database, acute rejection is no longer the most common cause of
hospitalization or allograft failure. Chronic rejection has now become the most common
cause of allograft failure and accounts for over 35% of allograft loss. Chronic rejection
is a complex clinical condition that includes both immunologic and non-immunologic causes
and is more accurately referred to as Chronic Allograft Nephropathy (CAN). Although
Calcineurin inhibitors (CNI) have played a central role in reducing acute rejection and
improving allograft survival, it has long been shown that they contribute to interstitial
fibrosis and chronic allograft nephropathy. Recent trials in adult transplantation have
demonstrated that with the use of the TOR-inhibitor, Sirolimus, it is possible to withdraw
Calcineurin inhibitors with no increase in rejection and with improvements in allograft
function, interstitial fibrosis and long term survival (1). We hypothesize that the use of
Sirolimus (SRL) in pediatric kidney transplantation will allow the withdrawal of Calcineurin
inhibitor and improved kidney function and long term survival. We plan to enroll 50
patients at the time of transplantation. Patients will receive routine immunosuppression of
CNI (Prograf), Mycophenolate mofetil (Cellcept) and prednisone. Those patients with normal
function and no rejection episodes after 6 months of transplantation will undergo a slow
conversion from Prograf to Sirolimus (Rapamune). We will then assess the rate of rejection,
allograft function, fibrosis on biopsy, and allograft survival over the following 18 months.

Inclusion Criteria at Transplant:

- Age < 19 years (up to the day of the 19th birthday)

- Panel Reactive Antibody Level (PRA) <20% (Flow cytometry method)

- Recipient of first living donor or deceased donor renal transplantation

- Signed and dated informed consent (per local IRB standards)

Exclusion Criteria at Transplant:

- Recipients of multi-organ transplants (e.g. kidney/pancreas transplant, etc.)

- Peak PRA > 20% at any time

- Recipient of en-bloc kidneys

- Recipient of an organ from an HLA identical donor or a non-heart beating donor

- Pregnant or lactating

- Positive for HIV or an immunodeficiency virus

- History of malignancy

- Use of investigational agents within 4 weeks prior to transplantation

- Current use of terfenadine, cisapride, astemizole, or pimozide (unless discontinued
before administration of SRL)

- Known hypersensitivity to sirolimus

- Known hypersensitivity to Prograf, Cellcept, prednisone, Cremophor, HCO-60, or murine
products