• Rate of acute rejection in all enrolled participants following sirolimus withdrawal [ Time Frame: transplantation to end of study ] [ Designated as safety issue: Yes ]
• acute rejection rate between initiation of sirolimus withdrawal and end of study [ Time Frame: initiation of sirolimus to end of study ] [ Designated as safety issue: Yes ]
• time from transplantation to acute rejection in participants for whom sirolimus withdrawal is not initiated [ Time Frame: transplantation to acute rejection ] [ Designated as safety issue: No ]
• time from transplantation to acute rejection in participants for whom acute rejection occurred in the 1 year post-transplant period [ Time Frame: Transplantation to acute rejection 1-year post-transplant ] [ Designated as safety issue: No ]
• time from transplantation to acute rejection in participants for whom sirolimus withdrawal has been initiated [ Time Frame: Transplantation to acute rejection ] [ Designated as safety issue: No ]
• incidence rate of death, graft loss, or severe acute rejection, stratified by sirolimus withdrawal status [ Time Frame: Transplantation to acute rejection ] [ Designated as safety issue: Yes ]
• incidence and severity of acute rejections, stratified by sirolimus withdrawal status [ Time Frame: Transplantation to acute rejection ] [ Designated as safety issue: Yes ]
• proportion of participants requiring anti-lymphocyte therapy (OKT3, ATG) for an acute rejection, stratified by sirolimus withdrawal status [ Time Frame: Transplantation to acute rejection ] [ Designated as safety issue: Yes ]
• safety, including incidence of post-transplant infections, malignancies, and side effects associated with conventional immunosuppression [ Time Frame: Transplantation to end of study ] [ Designated as safety issue: Yes ]
• renal function as measured by serum creatinine, stratified by sirolimus withdrawal status [ Time Frame: Transplantation to end of study ] [ Designated as safety issue: Yes ]

• Rate of acute rejection in all enrolled participants following sirolimus withdrawal
• acute rejection rate between initiation of sirolimus withdrawal and end of study
• time from transplantation to acute rejection in participants for whom sirolimus withdrawal is not initiated
• time from transplantation to acute rejection in participants for whom acute rejection occurred in the 1 year post-transplant period
• time from transplantation to acute rejection in participants for whom sirolimus withdrawal has been initiated
• incidence rate of death, graft loss, or severe acute rejection stratified by sirolimus withdrawal status
• incidence and severity of acute rejections, stratified by sirolimus withdrawal status
• proportion of participants requiring anti-lymphocyte therapy (OKT3, ATG) for an acute rejection, stratified by sirolimus withdrawal status
• safety, including incidence of post-transplant infections, malignancies, and side effects associated with conventional immunosuppression
• renal function as measured by serum creatinine, stratified by sirolimus withdrawal status

Transplant rejection occurs when a patient's body does not recognize the new organ and attacks it. Patients who have kidney transplants must take drugs to prevent transplant rejection. Alemtuzumab is a man-made antibody used to treat certain blood disorders. The purpose of this study is to test the safety and effectiveness of using alemtuzumab in combination with two other drugs, sirolimus and tacrolimus, to prevent organ rejection after kidney transplantation. This study will also test whether this combination of medications will allow patients to eventually stop taking antirejection medications entirely.

Study hypothesis: A new strategy of immunosuppression using alemtuzumab, tacrolimus, and sirolimus for human renal transplantation will permit a step-wise withdrawal from immunosuppressive drugs.

Drugs that suppress the immune system, such as sirolimus and tacrolimus, have contributed to increased success of transplantation. However, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, and these drugs make patients more susceptible to infection, endangering their health and survival. Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. This study will determine the effects of intravenous alemtuzumab and oral sirolimus and tacrolimus after kidney transplantation. The study will also evaluate this regimen's potential to allow eventual discontinuation of components of long-term immunosuppressive therapy.

This study will last up to 4 years. Participants will undergo kidney transplantation on Day 0 and will receive intravenous doses of alemtuzumab, acetaminophen, and diphenhydramine on Days 0, 1, and 2, as well as methylprednisolone on Day 0. After transplant, patients will receive up to 10 days of intravenous valganciclovir or acyclovir. Participants will take tacrolimus daily by mouth for at least 60 days after transplant and sirolimus daily by mouth for at least 12 months after transplant. As part of opportunistic infection (OI) prophylaxis, participants will also take sulfamethoxazole-trimethoprim by mouth 3 times a week, IV valganciclovir or acyclovir for up to 10 days post-transplant, and clotrimazole or nystatin by mouth for at least 3 months post-transplant.

There will be a minimum of 62 study visits spread out over 4 years after transplant. Vital signs measurement, adverse event and OI reporting, medication history, physical exam, and blood collection will occur at selected visits. Sirolimus withdrawal will begin when a participant meets certain study criteria. The withdrawal process will occur over a minimum of 3 months at an approximate rate of 33% of the pre-withdrawal dose per month. Participants eligible for sirolimus withdrawal will undergo several kidney biopsies, including one 2 weeks prior to the start of withdrawal, 6 and 12 months after completion of withdrawal, 1 year after study enrollment, and annually thereafter.

• Kidney Transplantation
• Kidney Disease

• Drug: Alemtuzumab
• Drug: Sirolimus
• Drug: Tacrolimus
• Procedure: Kidney transplant

• First MR. Tacrolimus based immunosuppression. J Nephrol. 2004 Nov-Dec;17 Suppl 8:S25-31. Review.
• Gourishankar S, Turner P, Halloran P. New developments in immunosuppressive therapy in renal transplantation. Expert Opin Biol Ther. 2002 Jun;2(5):483-501. Review.
• Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru S, Jamieson NV, Hale G, Waldmann H, Calne R. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation--efficacy and safety at five years. Am J Transplant. 2005 Jun;5(6):1347-53.

Inclusion Criteria

• Kidney transplant with primary cadaveric or non-HLA-identical living donor kidney (0-3 HLA-antigen mismatch)
• Receiving only a kidney and no other organs
• Able to take medications by mouth
• Willing to use acceptable methods of contraception

Exclusion Criteria

• Received HLA-identical living-donor kidney transplant
• HLA-antigen mismatch greater than 3
• Panel reactive antibody (PRA) value greater than 10% at any time prior to enrollment
• Received a non-heart-beating donor allograft
• Received a kidney from a donor who is greater than 60 years of age
• End-stage renal disease (ESRD) due to focal segmental glomulerosclerosis (FSGS)
• Previous kidney transplant
• Received multiorgan transplant
• Concomitant systemic corticosteroid therapy for other medical diseases
• Known hypersensitivity to alemtuzumab, tacrolimus, methylprednisolone, or sirolimus
• HIV infected
• Hepatitis C virus infected
• Positive for hepatitis B surface antigen
• Received dual or en-bloc pediatric kidneys
• Anti-human globulin (AHG) or T cell crossmatch positive
• Investigational drug within 6 weeks of study entry
• Known clinically significant cardiovascular or cerebrovascular disease
• Previous or current history of cancer or lymphoma. Patients with adequately treated basal or squamous cell skin carcinoma are not excluded.
• Clinically significant coagulopathy or a requirement for chronic anti-coagulation therapy precluding biopsy
• CMV-negative recipient, if received kidney is from a CMV-positive donor
• History of a psychological illness or condition that, in the opinion of the investigator, may interfere with the study
• Graves disease. Patients who have been previously adequately treated with radioiodine ablative therapy are not excluded.
• Active systemic infections
• Platelets less than 100,000 cells/mm3 at study entry
• Pregnant or breastfeeding