Inducing Graft Tolerance in HLA Haplotype Matched Related and 3 Ag Matched Unrelated Living Donor Kidney Transplantation

The objectives of this study are to determine whether patients undergoing kidney transplants
for end stage renal disease (ESRD) can be taken off immune suppression drugs given to prevent
kidney rejection or can be maintained on low dose immune suppression while maintaining normal
kidney function. Patients will receive blood stem cell transfusions from their donors 11 days
after transplant to reduce the risk of graft rejection while tapering the post-transplant
immune suppression drug regimen. Patients will be treated with total lymphoid irradiation
(TLI) and rabbit anti-thymocyte globulin (rATG) followed by transfusion of enriched CD34+
hematopoietic cells containing blood stem cells and CD3+ T cells from their donors in order
to induce blood cell mixed chimerism. These chimeric patients produce blood cells from both
their own and their donors' blood stem cells. Donors will have blood collected by apheresis
after treatment with drugs to "mobilize" blood stem cells from their bone marrow. Collection
of the donor's cells will occur 6-8 weeks before kidney donation surgery. After transplant,
patients will receive a 14 week course of corticosteroid therapy (e.g., Prednisolone) with
gradual dose reduction. They will also receive a 12 month course of mycophenolate mofetil
(MMF) with dose tapering beginning 9 months post-transplant and an 18 month course of
Tacrolimus with tapering also beginning at 9 months post-transplant. Patients will be
monitored for renal function, mixed blood cell chimerism, the appearance of donor specific
antibodies (DSA) from their own immune cells reacting to the transplanted kidney, and
evidence of rejection in any biopsies of the donor kidney after transplant. Immune
suppression drug withdrawal will begin and continue as long as mixed chimerism is maintained,
the patient shows no evidence of graft versus host disease (GVHD), the transplanted kidney
functions well, and there is no indication of kidney rejection in biopsies. Patients not
meeting these criteria will be maintained on low dose immunosuppressive drug therapy unless
more extensive treatments are needed to prevent rejection. Potential candidates need to be
approved for kidney transplant under this protocol and available for close follow-up
post-transplant. This study, sponsored by the California Institute for Regenerative Medicine
(CIRM), is being conducted in parallel with NCT01165762 sponsored by the National Institutes
of Health with distinct reporting and separation of funding support for the patients enrolled
under each sponsor.

Inclusion Criteria:

1. All consenting adults (18 years of age) living donor renal transplant recipients at
Stanford University Medical Center who have a one haplotype match donor.

2. Patients who agree to participate in the study and sign an Informed Consent.

3. Patients who have no known contraindication to administration of rabbit ATG or
radiation.

4. Males and females of reproductive potential who agree to practice a reliable form of
contraception for at least 24 months posttranplant.

Exclusion Criteria:

1. Previous treatment with rabbit ATG or known allergy to rabbit proteins.

2. History of malignancy with the exception of non-melanoma skin malignancies.

3. Pregnant women or nursing mothers.

4. Serological evidence of HIV, Hepatitis B or Hepatitis C infection.

5. Seronegative for Epstein-Barr virus , if donor is seropositive.

6. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (with a
platelet count < 100,000/mm3)

7. Panel Reactive antibody greater then 20% or demonstration of donor specific antibody
(DSA).

8. Prior organ transplantation.

9. High risk of primary kidney disease recurrence (i.e. primary FSGS).