CRISPR-Edited HLA Donor Kidney Transplant to Reduce Rejection Risk

Inclusion Criteria: * Adult patients, age 16 to 85 years, with end-stage renal disease (ESRD) who are candidates for kidney transplantation. This includes patients on dialysis or approaching dialysis who have been evaluated and listed for transplant. * Eligible for transplant surgery based on medical assessment (i.e., no contraindications to major surgery and transplantation). The patient's overall health status must be sufficient to undergo the transplant procedure and the required immunosuppression. * Suitable donor organ available: A deceased-donor kidney that meets standard acceptable criteria for transplant (e.g., adequate organ function and anatomy) and is ABO blood type compatible with the recipient. The donor kidney must be allocated to the trial and available for ex vivo gene editing prior to transplantation. * Informed consent: The patient (or legally authorized representative) is able to understand the experimental nature of the study and has voluntarily signed the informed consent form. The patient must be willing to comply with all study procedures, follow-up visits, and laboratory tests. * Negative crossmatch (if applicable): No pre-existing anti-donor reactivity that would cause immediate graft failure. (All recipients should have a negative T and B cell crossmatch with the donor organ prior to transplant, as per standard practice, to ensure no strong baseline donor-specific antibodies, especially against any remaining donor HLA such as HLA-C.) * Women of childbearing potential must have a negative pregnancy test and must agree to use effective contraception during the study and for a period after (to be specified, e.g., 1 year post-transplant), given the use of immunosuppressants and the unknown effects of gene-edited organ transplantation on pregnancy. Men with partners of childbearing potential should also agree to use contraception. * High immunologic risk patients are eligible: Patients with high panel reactive antibody (PRA) levels or a history of sensitization (from prior transplants, blood transfusions, or pregnancies) are allowed and even anticipated in this trial, as the intervention is designed to benefit patients with broad HLA sensitization. For instance, patients with calculated PRA \> 80% (who have difficulty finding matched donors) can be included. (Such patients must still meet the crossmatch criterion above - any existing antibodies should not target the antigens remaining on the edited graft.) * Geographic availability: Patients must be available for long-term follow-up in the study center in China or able to travel for scheduled follow-up visits. They should be willing to remain in proximity to the transplant center for the initial post-operative period as per standard transplant care. Exclusion Criteria: * Active infection: Any ongoing severe infection that would contraindicate transplantation or be exacerbated by immunosuppression (e.g., active tuberculosis, untreated Hepatitis B or C, HIV with uncontrolled viremia, etc.). Patients with controlled HIV (on stable antiretroviral therapy with undetectable viral load) may be considered on a case-by-case basis, but active uncontrolled infection is excluded. * Pregnancy or breastfeeding: Pregnant women are excluded due to the need for immunosuppressive drugs and the unknown risks of the investigational intervention on a fetus. Women who are breastfeeding are also excluded due to potential drug excretion in milk and unknown risks to the infant. * Multi-organ transplant need: Patients requiring more than one organ transplant simultaneously (e.g., kidney + liver, or kidney + heart) are excluded, as this trial focuses on isolated kidney transplant outcomes. (A history of a prior transplant is not an automatic exclusion if the patient now only needs a kidney, but concurrent multi-organ requirements are excluded.) * Severe co-morbidities that would significantly increase transplant risk or confound results: for example, uncontrolled cardiovascular disease (e.g., recent myocardial infarction, severe heart failure), uncontrolled diabetes with end-organ damage beyond ESRD, severe liver dysfunction, or other life-threatening illnesses unrelated to kidney failure. Such conditions could make the surgery unsafe or the outcome hard to interpret. * Contraindications to immunosuppression: Patients with conditions that preclude standard immunosuppressive therapy (for instance, a history of anaphylaxis to tacrolimus or mycophenolate that cannot be managed, or chronic infection that would be fatally worsened by immunosuppression) are excluded. The trial still relies on baseline immunosuppressants, so patients must be able to tolerate them. * Inability to follow the protocol: Patients with significant psychiatric disorders, cognitive impairment, or social situations that would make adherence to the study protocol and follow-up unlikely. This includes inability to give informed consent or lack of support for the intensive follow-up (for example, if the patient is incarcerated or has no fixed address, etc.). * Prior gene therapy or organ experiment participation: Patients who have previously received any investigational gene therapy, or who have a donor-specific tolerance induction or other experimental transplant treatments ongoing, may be excluded to avoid confounding effects. (This is a precaution to attribute outcomes specifically to the CRISPR-edited organ intervention.) * Laboratory abnormalities: Any clinically significant abnormalities in baseline labs that would pose added risk - for instance, severe leukopenia or thrombocytopenia that could worsen with immunosuppression, or uncontrolled coagulopathy that raises surgical risk. * Donor-related exclusions: If the donor kidney, upon retrieval, is found unsuitable for gene editing or transplant (e.g., poor organ quality, unexpected disease in the organ, or if the CRISPR editing fails to achieve sufficient knockout of target genes), the transplant to that patient will not proceed under the study (the patient may either receive a standard transplant off-study or wait for another opportunity). In such a case, the patient might be withdrawn or deferred, but this is a procedural consideration rather than a characteristic of the patient.