The goal is to investigate the safety of the conditioning regimen, and its ability to induce donor/recipient lymphohematopoietic chimerism without Chimerism Transition Syndrome (CTS), which may result in donor-specific unresponsiveness (tolerance) to the renal allograft in the absence of maintenance immunosuppression.

Inclusion Criteria:

• Male or female 18-65 years of age.
• Candidate for a living-donor renal allograft from an HLA mismatched donor
• Subjects with chronic kidney disease stage or ESRD who are treated with either hemodialysis or peritoneal dialysis.
• First transplant.
• Use of FDA-approved methods of contraception
• Ability to understand and provide informed consent.
• Negative COVID at screening and 2 days before procedure

Exclusion Criteria:

• ABO blood group-incompatible renal allograft.
• Participant with a (non DSA) PRA > 20% 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.
• Active 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
• History of cancer (following the American Transplant Society Guidelines)
• Underlying renal disease etiology with a high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis).
• Prior dose-limiting radiation therapy
• 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
• 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).
• Allergy or sensitivity to any component of Siplizumab, Fludarabine, Cyclophosphamide, tacrolimus, DMSO, MMF or rituximab.
• The presence of any medical condition that the investigator deems incompatible with participation in the trial.
• Subjects who have non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c<7). Subject with severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities will be excluded from the study