This study will test the safety and effectiveness of two drugs, Sirolimus and Thymoglobulin,
for preventing rejection of transplanted kidneys. Standard anti-rejection therapy uses a
combination of drugs, such as cyclosporine, tacrolimus, azathioprine, steroids, and others,
that are taken daily for life. However, even with this daily therapy, more than half of
kidney recipients slowly reject their transplant within 10 years. Both Thymoglobulin, an
antibody, and Sirolimus, an anti-rejection drug, prevent rejection by lowering the response
of the immune system to the transplanted organ. Thymoglobulin is given in the pre- and
postoperative period, and Sirolimus is taken long term.
Patients who receive a kidney transplant at the National Institutes of Health Clinical
Center are eligible for this study. Candidates will be screened with a medical history,
physical examination, and blood and urine tests.
Participants will undergo a kidney transplant. Before the surgery, a central line
(intravenous catheter), through which blood and medicine can be given, is placed in the neck
or chest. Patients may also undergo leukapheresis, a procedure for collecting white blood
cells. The cells can be stored for transfusion later if white cell counts drop following
Thymoglobulin treatment. For this procedure, blood is drawn from a needle placed in the arm
and flows into a machine that separates the blood components by spinning. The white cells
are collected in a bag and the red cells and plasma are returned through a second needle in
the other arm.
Thymoglobulin will be given intravenously the day before the transplant and days 1 through 9
after the operation. Sirolimus will be taken by mouth, mixed with water or orange juice.
Sirolimus therapy starts the day of the transplant and continues for life.
Follow-up study visits will be scheduled weekly for the first month after the transplant,
then every 6 months for 1 year and then once a year for 4 years. Procedures during these
visits may include blood and urine tests, physical examination, and check of vital signs
(i.e., blood pressure, heart rate, breathing rate, temperature). Kidney biopsies (removal
of a small piece of tissue for examination under the microscope) will be done at 2 weeks, 1
month and 6 months after surgery and then yearly for 4 years to check for any damage to the
kidney. In addition, a local doctor will do routine laboratory tests 2 to 3 times a week
for the first 2 to 3 months aft...
This protocol will test a novel dual agent combination therapy for its ability to prevent
human renal allograft rejection. Thymoglobulin (Sangstat), a FDA-approved polyclonal
rabbit-IgG antithymocyte preparation, will be given for ten days at the time of
transplantation to achieve profound lymphocyte depletion. This will be paired with chronic
therapy with Sirolimus (rapamycin, Wyeth-Ayerst), an oral immunosuppressant agent recently
approved by the FDA. Rapamycin allows for antigen specific T cell activation but prevents T
cell clonal expansion by interrupting IL-2 receptor beta-chain signal transduction. The
rationale for this combination is to eliminate existing alloreactive T cell clones that
could initiate a rejection at the time of transplantation, and to promote graft specific
activation induced cell death (AICD) in repopulating T cells such that an allospecific T
cell deficit is induced. The desired effect of this therapy is to prevent allograft
rejection without the chronic use of calcineurin inhibitors or glucocorticosteroids, and in
doing so, develop a regimen for transplantation that avoids most of the chronic drug
toxicities inherent in the use of these two classes of immunosuppressants.
Twenty people will be evaluated in this pilot protocol. Ten will receive living donor
kidney allografts and ten will receive cadaveric kidney allografts. Patients will be
treated with Thymoglobulin beginning prior to graft implantation and continuing for ten
days. Glucocorticosteroids will be given during the Thymoglobulin treatment to limit
monocyte activation and prevent the cytokine release syndrome associated with this antibody
preparation. Patients will be given Sirolimus orally beginning the day after
transplantation and continuously thereafter. Patients will then be monitored for evidence
of allograft rejection using standard functional parameters and protocol allograft biopsies.
In addition, patients will be followed for a specific desired effect, allospecific AICD,
that should promote the development of allospecific graft tolerance. This will be
accomplished by assaying peripheral blood and allograft biopsies for apoptosis and
peripheral blood for evidence of alloreactive T cell clone depletion.
- INCLUSION CRITERIA:
Candidates for a kidney transplant performed at the NIH 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 enrolled on the Clinical
Center Living Donor Protocol who consents to periodic phlebotomy for peripheral blood
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 a 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.
Significant coagulopathy or requirement for anticoagulation therapy that would
contraindicate protocol allograft biopsies.
Platelet count less than 100,000/mm(3).
Any known immunodeficiency syndrome.
Any history of cardiac insufficiency, major vascular disease, symptomatic coronary artery
Systemic or pulmonary edema.
Inability to be effectively dialyzed.
Any condition that 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.
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