This study will test the safety and effectiveness of a combination of three drugs followed
by long-term treatment with just one drug in preventing organ rejection in kidney transplant
patients. Current anti-rejection medicines are not completely effective in preventing
rejection. This trial will test how well Thymoglobulin, Tacrolimus, and Sirolimus work
together post-transplant and if the treatment can be reduced over time to control rejection
with either Tacrolimus or Sirolimus alone.
Candidates for kidney transplantation at the National Institutes of Health Clinical Center
may participate in this 5-year study. Patients will be screened for eligibility with a
medical history, physical examination, and blood tests.
Participants will undergo the following tests and procedures:
- Central line placement: A large intravenous catheter (plastic tube, or IV line) is
placed in a vein in the chest or neck under local anesthesia before the transplant
surgery. The line remains in place for some time during the hospitalization to
administer Thymoglobulin, antibiotics, and blood, if needed. The line is also used to
collect blood samples.
- Leukapheresis: This procedure for collecting white blood cells is done before the
transplant. The cells are studied to evaluate the patient's immune system. Whole blood
is withdrawn through a catheter in an arm vein or through the central line and directed
into a machine that separates the blood components by spinning. The white cells are
removed and the red cells and plasma are returned to the body.
- Kidney transplant: Patients undergo kidney transplant surgery under general anesthesia.
- Immunosuppressive therapy: Patients receive thymoglobulin by vein for 4 days starting 1
day before the transplant. They also take Tylenol, Benadryl and a steroid
(methylprednisolone) to help reduce the side effects of the Thymoglobulin. After the
transplant, patients receive Tacrolimus and Sirolimus by mouth once a day for 6 months
and then either Tacrolimus or Sirolimus alone indefinitely. In addition, they take
medicines to help prevent viral and fungal infections for 6 months because the
immunosuppressive therapy leaves them vulnerable to infection.
- Follow-up visits: After hospital discharge, patients return to the Clinical Center
twice a week for 4 weeks, then every 6 months for 1 year, and then yearly for another 4
years. At each visit, the patient's vital signs are checked and blood and urine samples
are collected. Periodically, patients are also questioned about how they feel and how
the transplant has affected their quality of life. Kidney biopsies (removal of a small
amount of kidney tissue through a thin needle) are done when the patient begins
single-drug immunosuppression (generally 6 months after transplantation) and 1 year
after that. The biopsied tissue is examined to evaluate how well the kidney is
responding to the treatment and to determine how to proceed with therapy.
- Routine laboratory tests: Routine tests, coordinated by the patient's local physician,
are done 2 to 3 times a week for the first 2 to 3 months after transplantation, then
weekly for several more months, and at least monthly for life.
This protocol facilitates the development of methods for determining whether transplant
recipients have developed immune hyporesponsiveness or tolerance towards their allograft.
These methods will involve the study of peripheral blood or biopsy tissue obtained at
regular intervals from patients receiving kidney or combined kidney-pancreas allografts at
the NIH Clinical Center. In addition, patients that have previously received a kidney or
combined kidney-pancreas allograft will be evaluated using assays requiring peripheral blood
mononuclear cells and/or biopsies. Assays developed under this protocol will be used in
subsequent protocols to assess the effects of immune modulating treatment regimens and may
eventually be used to direct clinical care or guide the withdrawal of immunosuppressive
agents. However, patients enrolled in this protocol will not have any change in treatment
based solely on the assays developed without being enrolled in an additional study.
- INCLUSION CRITERIA:
Candidates for a kidney transplant at the Clinical Center.
Willingness and legal ability to give informed consent.
Availability of donor tissue for testing. This could include splenic or peripheral blood
lymphocytes from a cadaveric donor or a willing living donor who consents to periodic
phlebotomy for peripheral blood lymphocyte isolation.
Immunosuppressive drug therapy at the time of or 2 months prior to enrollment.
Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus,
azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide,
methotrexate, or other agents whose therapeutic effect is immunosuppressive.
Any active malignancy or any history of any hematogenous malignancy or lymphoma. Patients
with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the
lesions are appropriately treated prior to transplant.
Any known immunodeficiency syndrome, or other condition that, in the opinion of the
investigators, would likely increase the risk of protocol participation or confound the
interpretation of the data.
Any history of sensitization to rabbits or extensive exposure to rabbits, as defined by
symptomatic allergic response upon exposure to rabbits.
Inability or unwillingness to comply with protocol monitoring and therapy including, among
others, a history of noncompliance, circumstances where compliance with protocol
requirements is not feasible due to living conditions, travel restrictions, access to
urgent medical services, or access to anti-rejection drugs after the research protocol is
Peak Panel Reactive Antibody greater than 20%, or historically positive crossmatch due to
HLA identity between the donor and recipient.
Pregnancy or unwillingness to practice an approved method of birth control. Acceptable
methods of birth control may include barrier methods (condom and/or diaphragm with
spermicide), oral contraceptives, Norplant, Depo-Provera or partner sterility.