Study of Combined Kidney and Blood Stem Cell Transplant From a Brother or Sister Donor (OneLegacy)

Recipient Inclusion Criteria:

1. Males and females ages 18 years and older receiving living donor kidney transplant from an HLA-identical sibling at UCLA Medical Center.
2. Agrees to participate in the study and is able to give informed consent.
3. Resides or is willing to stay within 3 hours distance from UCLA Medical Center by ground transportation for the first three to six months of the trial at the physician's discretion.
4. Meets institutional criteria for kidney and HSPC transplant.
5. No known contraindication to administration of rATG or radiation.
6. If patient is a female of reproductive potential (i.e., no documented absence of ovaries or uterus, history of tubal ligation, or post-menopausal status) patient must be confirmed not pregnant by a serum or urine pregnancy test) and must agree to practice a reliable form of contraception including hormonal treatments, barrier methods or intrauterine device for at least 12 months post-transplant. Karnofsky Performance Score ≥ 70.
7. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 40% by MUGA (Multi Gated Acquisition) scan or echocardiogram.
8. Adequate pulmonary function defined as FVC and DLCO of greater than or equal to 50% of predicted.
9. Adequate liver function defined as total bilirubin ≤ 1.5 times the upper limit of normal and AST/ALT ≤ 2.0 times the upper limit of normal.
10. Adequate social support based on evaluation by the UCLA renal transplant team licensed clinical social worker.

Recipient Exclusion Criteria:

1. Donor is identical twin.
2. ABO incompatibility with donor.
3. Previous solid organ transplant
4. Multi-organ transplantation
5. Previous treatment with rATG or a known allergy to rabbit proteins

6. History of active malignancy within the past 5 years with the exception of non-melanomatous skin cancer.

   a. History of another primary malignancy except for: i. Malignancy treated with curative intent and with no known active disease >2 years before the first dose of study treatment and of low potential risk for recurrence ii. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease iii. Very low risk and low risk cancer adequately treated or on active surveillance b. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, and DCIS)

7. Pregnant (confirmed by urine or serum pregnancy test) or lactating.
8. Leukopenia (with a white blood cell count < 3,000/ µL) or thrombocytopenia (with a platelet count < 100,000/ µL).
9. Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C).
10. Positive HLA DSA
11. Seropositivity for HIV 1, HIV 2, HTLVI, HTLV II
12. Active West Nile Virus infection
13. Renal disease with high risk of recurrence (i.e., focal segmental glomerulosclerosis).
14. Advanced hepatic fibrosis or cirrhosis secondary to hepatitis B and/or C diagnosis.
15. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; active extra-renal autoimmune disease requiring immunosuppression.
16. Active extra-renal autoimmune disease requiring immunosuppression.
17. Neuropsychiatric illness that precludes the ability to give informed consent and/or places the patient as high risk for non-compliance with the safety monitoring requirements of the study.
18. May not have received other immunosuppressive medications, including but not limited to alemtuzumab, belatacept, sirlolimus, everolimus, azathioprine, basiliximab, and eculizumab within six months of the study treatment. Use of corticosteroids prescribed for a time-limited indication (</= 4 weeks) and stopped at least 4 weeks before the kidney transplant is acceptable.
19. May not have received immunotherapy drugs such as immune checkpoint inhibitors (e.g. pembrolizumab, nivolumab, and ipilimumab), tumor necrosis factor inhibitors, rituximab, and interleukin-2 within six months of the study treatment.
20. Current or active abuse of alcohol and/or drugs within last 6 months.
21. BMI 40 or greater.

Donor Inclusion Criteria:

1. HLA-identical sibling on high-resolution HLA typing who is ≥18 years of age.
2. Meets institutional criteria for living kidney and allogeneic HSPC transplant donation.
3. Medically fit to tolerate peripheral blood apheresis, including weighing ≥110 pounds, hemoglobin ≥ 11 g/dL, white blood cell count ≥ 3,000/µL, and platelets ≥120,000/µL.
4. Normal serum chemistry and coagulation studies; or, if abnormal, the differences are not considered clinically significant.

Donor Exclusion Criteria:

1. Recipient is identical twin.
2. ABO incompatibility with recipient.
3. Medically unfit to tolerate peripheral blood apheresis (small body size, poor vascular access, not a suitable candidate for placement of a central catheter, etc.).
4. Pregnant (confirmed by urine or serum pregnancy test) or lactating.
5. Seropositivity for HIV 1, HIV 2, HTLV I, HTLV II
6. Active West Nile Virus infection
7. Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C)

8. Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study

   1. History of active malignancy within the past 5 years with the exception:Adequately managed malignancy within the past two years with low risk of recurrence may be acceptable as per clinician discretion
   2. Adequately managed non-melanoma skin cancer
   3. Adequately managed carcinoma in situ e.g., cervical cancer in situ, and DCIS
9. No current or recent use of oral anti-coagulants. (For the purpose of this study, recent is defined as less than 60 days prior to apheresis.). Note: Use of aspirin and non-steroidal anti-inflammatory drugs, for pain and inflammation management purposes, are permitted to enroll in the study, but these drugs must be stopped 14 days prior to apheresis, however subjects who are taking aspirin for its anti-platelet/anti-thrombotic effect, are excluded.