Tolerance Through Mixed Chimerism (Sip-Tego)

Recipient Inclusion Criteria:

1. Male or female 18-65 years of age.
2. Subjects with chronic kidney disease stage V (GFR<15ml/min/1.73m2) or ESRD who are treated or imminently be treated with either hemodialysis or peritoneal dialysis.
3. Candidate for a living-donor renal allograft from an HLA matched or mismatched donor
4. First or second renal transplant.
5. EBV Seropositive
6. Use of FDA-approved methods of contraception by all recipients from the time that study treatment begins until 104 weeks (24 months) after renal transplantation
7. Ability to understand and provide informed consent.
8. Negative COVID-19 test during screening and two days prior to procedure

Recipient Exclusion Criteria:

1. ABO blood group-incompatible renal allograft
2. Participant with a donor-specific antibody (DSA) within 6 months prior to transplant
3. Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (<100,000/mm3)
4. Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA); or positivity for hepatitis B surface antigen.
5. Untreated Infection
6. Left ventricular ejection fraction < 40% as determined by TTE or clinical evidence of heart failure.
7. Forced expiratory volume FEV1 or DLCO < 50% of predicted.
8. Lactation or pregnancy.
9. Patients with active cancer or those with a high risk of recurrence following the American Transplant Society
10. Underlying renal disease etiology with a high risk of disease recurrence in the transplanted kidney (such as non-genetic primary focal segmental glomerulosclerosis dense deposit disease, C3 glomerulonephritis, and, atypical hemolytic uremic syndrome).
11. Prior dose-limiting radiation therapy for treatment of malignant disease.
12. Known genetic disease or family history that may result in greater sensitivity to the effects of irradiation, or a physical deformity that would preclude adequate shielding or appropriate dosing during the irradiation component of the conditioning regimen. This includes long term cigarette smoking or a family history of malignancy.
13. Enrollment in other investigational drug studies within 30 days prior to enrollment.
14. Abnormal (>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) bilirubin, (c) coagulation studies (PT, PTT) , or any patients on chronic anticoagulation therapy.
15. Allergy or sensitivity to any component of Cyclophosphamide, ATGAM, tacrolimus, Siplizumab, Tegoprubart, or rituximab.
16. The presence of any medical condition that the investigator deems incompatible with participation in the trial. This includes a history of alcohol abuse or illicit drug use/dependence.
17. Any chronic or intermittent administration of immunosuppressant medication (such as for inflammatory bowel disease or asthma)
18. Subjects who have non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<8%). Subjects with severe diabetes-related complications, such as advanced retinopathy, gastroparesis, or severe neuropathy that significantly impair their ability to perform normal, independent daily activities, will also be excluded.

Donor Inclusion Criteria:

1. Male or female 18-70 years of age.
2. For females of childbearing potential: a serum pregnancy test showing negative results.
3. Excellent health per conventional pre-donor workup (medical and psychosocial evaluation)
4. Acceptable laboratory parameters (hematology in normal or near-normal range; Liver function <2 times the upper limit of normal, and normal creatinine).
5. Negative for viral infection with HBV (HbsAg and NAT), HIV (antibody and NAT), HCV (NAT), or HTLV-1.
6. Cardiac/pulmonary function within normal limits (CXR, ECG).
7. Ability to understand and provide informed consent.
8. Meets standard institutional criteria for bone marrow aspiration and kidney donation.
9. Negative COVID-19 test during screening and two days prior to procedure