Tolerance Through Mixed Chimerism (Sip-Tego)

Inclusion criteria

• Male or female 18-65 years of age.
• 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.
• Candidate for a living-donor renal allograft from an HLA matched or mismatched donor
• First or second renal transplant.
• EBV Seropositive
• 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
• Ability to understand and provide informed consent.
• Negative COVID-19 test during screening and two days prior to procedure Recipient

Exclusion criteria

• ABO blood group-incompatible renal allograft
• Participant with a donor-specific antibody (DSA) within 6 months prior to transplant
• Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (\<100,000/mm3)
• 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.
• Untreated Infection
• Left ventricular ejection fraction \< 40% as determined by TTE or clinical evidence of heart failure.
• Forced expiratory volume FEV1 or DLCO \< 50% of predicted.
• Lactation or pregnancy.
• Patients with active cancer or those with a high risk of recurrence following the American Transplant Society
• 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).
• Prior dose-limiting radiation therapy for treatment of malignant disease.
• 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.
• Enrollment in other investigational drug studies within 30 days prior to enrollment.
• 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.
• Allergy or sensitivity to any component of Cyclophosphamide, tacrolimus, Siplizumab, Tegoprubart, or rituximab.
• 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.
• Any chronic or intermittent administration of immunosuppressant medication (such as for inflammatory bowel disease or asthma)
• 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:
• Male or female 18-70 years of age.
• For females of childbearing potential: a serum pregnancy test showing negative results.
• Excellent health per conventional pre-donor workup (medical and psychosocial evaluation)
• Acceptable laboratory parameters (hematology in normal or near-normal range; Liver function \<2 times the upper limit of normal, and normal creatinine).
• Negative for viral infection with HBV (HbsAg and NAT), HIV (antibody and NAT), HCV (NAT), or HTLV-1.
• Cardiac/pulmonary function within normal limits (CXR, ECG).
• Ability to understand and provide informed consent.
• Meets standard institutional criteria for bone marrow aspiration and kidney donation.
• Negative COVID-19 test during screening and two days prior to procedure