Immunological Tolerance in Patients With Mismatched Kidney Transplants

Recipient Inclusion Criteria: 1. Age 18 and older 2. Receiving an HLA single haplotype-matched related living donor or 0-3 antigen (at A, B, C, DR) HLA mismatched unrelated living donor combined kidney and hematopoietic stem cell transplant (the first six subjects will be HLA single haplotype-matched; the final two subjects may be either HLA single-haplotype-matched or 0-3 antigen (at A, B, C, DR) HLA mismatched) 3. Agreement to participate in the study and ability to give informed consent 4. Meets institutional criteria for kidney and allogeneic hematopoietic stem cell transplant 5. Resides or is willing to stay within 3 hours distance from University of California, Los Angeles Medical Center by ground transportation for the first six months post-kidney transplant 6. No known contraindication to administration of rATG or radiation 7. If a 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 pregnancy 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 duration of the study 8. Males of reproductive age must consent to use reliable and effective methods to avoid pregnancy 9. Karnofsky Performance Score (KPS) ≥ 70 10. Adequate cardiac function defined as left ventricular ejection fracture (LVEF) ≥ 40% by Multi Gated Acquisition (MUGA) scan or echocardiogram 11. Adequate pulmonary function defined as FVC and DLCO of ≥ 50% of predicted 12. 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 13. Adequate social support based on evaluation by the UCLA renal transplant team licensed clinical social worker 14. Negative test for COVID 19 by RT -PCR and/or have received COVID 19 vaccinations. Subjects who have not received their COVID-19 vaccination may be enrolled on the trial based on clinical judgement. Recipient Exclusion Criteria: 1. ABO incompatibility with donor 2. Previous solid organ transplant 3. Multi-organ transplantation 4. Previous treatment with rATG or a known allergy to rabbit proteins 5. Previous treatment with belumosudil (KD025) 6. History of active malignancy within the past 5 years with the exception of: 1. Low risk cancer on active surveillance 2. Malignancy treated with curative intent with no known active disease \>2 years before the first dose of study treatment and of low potential risk of recurrence 3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease 4. 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. INR and/or PTT ≥ 1.5X upper limits of institutional normal 10. Positive HLA DSA 11. Active bacterial, fungal, mycobacterial, or viral infection (including active hepatitis B and/or C, or West Nile Virus) 12. Seropositivity for HIV 1, HIV 2, HTLV-1 or HTLV-II 13. Renal disease with high risk of recurrence (i.e., focal segmental glomerulosclerosis) 14. Advanced hepatic fibrosis or cirrhosis 15. Congestive heart failure, symptomatic coronary artery disease, and/or uncontrolled cardiac arrhythmia 16. Active extra-renal autoimmune disease requiring immunosuppression 17. Neuropsychiatric or medical 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 immunosuppressive medications within one year 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 or immunomodulatory drugs such as immune checkpoint inhibitors, tumor necrosis factor inhibitors, rituximab, intravenous immune globulin, and interleukin-2 within one year of the study treatment 20. Current or active abuse of alcohol and/or drugs within the last 6 months 21. Body Mass Index (BMI) ≥ 40 22. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. 23. ESRD patients with the following etiologies 1. Autoimmune disease including lupus 2. Vasculitis involving the kidney (such as Wegener's Granulomatosis 3. Thrombotic Thrombocytopenic Purpura 4. Alport's syndrome (due to increased risk of developing post-transplant Anti-Glomerular Basement Membrane Disease (Anti-GBM Disease)) 24. HgbA1c ≥10 25. Prior history of radiation therapy 26. History of ≥ 20 pack per year smoking. a. Patients must be abstinent from tobacco use for ≥ 6 months prior to transplantation Donor Inclusion Criteria: 1. Age 18 or older 2. HLA single haplotype-matched related living donor or 0-3 Antigen (at A, B, C, DR) HLA mismatched unrelated living donor 3. Meets institutional criteria for living kidney and allogeneic HSPC transplant donation 4. Medically fit to tolerate peripheral blood apheresis, including 1. Weight ≥ 110 pounds 2. Hemoglobin ≥ 11 3. White blood cell count ≥ 3,000/µL 4. Platelets ≥ 120,000/µL 5. Normal serum chemistry and coagulation parameter studies; or, if abnormal, the changes are not considered clinically significant 6. Negative test for COVID 19 by RT -PCR and/or have received COVID 19 vaccinations. Subjects who have not received their COVID-19 vaccination may be enrolled on the trial based on clinical judgement. Donor Exclusion Criteria 1. ABO incompatibility with recipient 2. Medically unfit to tolerate peripheral blood apheresis (small body size, poor vascular access, not a suitable candidate for placement of a central catheter, etc.) 3. Pregnant (confirmed by urine or serum pregnancy test) or lactating 4. Seropositivity for HIV 1, HIV 2, HTLV-I or HTLV-II 5. Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C, West Nile Virus) 6. Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study 7. History of active malignancy within the past 5 years with the exception: 1. 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 8. 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). Aspirin and non-steroidal anti-inflammatory drugs must be stopped 14 days prior to apheresis. 9. Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data