In this pilot/feasibility trial the investigators will assess the feasibility of the trial design described below and perform a pilot study to obtain information for the design of a future multicenter randomized controlled trial (RCT). These goals will be achieved within the three year span of this program. The study has organized the investigator team to be able to achieve the following goals: 1) obtain regulatory approval, 2) optimize the clinical trial design, 3) recruit patients, 4) conduct the study, including optimization of immunosuppression regimen and monitoring the endpoints of interest, 5) conduct statistical analysis of the results, and 6) analyze the findings. Thirty-four subjects will be recruited at the time of kidney transplantation. Inclusion and exclusion criteria are listed below. All subjects will be started with institutional standard of care (SOC): quadruple immunosuppressive therapy with in-duction (basiliximab or antithymocyte globulin), tacrolimus, steroids, and mycophenolate mofetil/mycophenolic acid (MMF/MPA). Maintenance immunosuppression after transplantation will also be determined by the center per SOC. At recruitment, one month after transplantation, subjects without biopsy proven rejection will be recruited and enrolled in the baseline monitoring period of the study. Monitoring includes weekly dd-cfDNA (donor-derived cell-free DNA) measurements, drawn at the same time as SOC labs, up to three months after transplantation. Subjects will continue to be seen per clinical SOC Both SOC and dd-cfDNA labs will be obtained per patient preference (commercial lab, mobile phlebotomy, or at UF). Dd-cfDNA assessments will be performed at a Clinical Laboratory Improvement Amendments (CLIA)-approved centralized location per company standards. Clinical SOC includes an updated history and physical, including a full medication history, biochemical and hematological measurements, and drug exposure of tacrolimus monitored by obtaining trough level measurements. Three months after transplantation, a graft biopsy will be obtained and analyzed by an expert renal pathologist. Patients with evidence of rejection on biopsy will be excluded. Patients without rejection (Banff Classification 2018 active or chronic cellular or antibody mediated rejection) will undergo balanced randomization (1:1) to one of the following treatment arms:

1. Control arm: Subjects will continue per SOC, where the management of their immunosuppression regimen will be determined by their physician per center practices, including dd-cfDNA data.
2. Treatment arm: Subjects will have dd-cfDNA data analyzed by PPM. Data, such as drug levels and regimens, will be used to fit a 2nd order polynomial for each patient to build patient-specific dose-response pro-files with covariates that include the administered drugs tacrolimus, steroids, and MMF/MPA. PPM will be used to derive an optimal combination of tacrolimus, MMF/MPA, and prednisone to achieve minimal renal allograft injury, while staying within the therapeutic range of the medications. All else being equal, the most efficacious combination with the lowest dose of tacrolimus will be utilized.

In either arm, if a change is made in the immunosuppression regimen, SOC and dd-cfDNA labs will be obtained one week later to assess for changes and for the regimen to be adjusted accordingly. If no change is made in the immunosuppression regimen, the subject will continue with their SOC labs and clinic visit schedule. All subjects will undergo a protocol biopsy at the completion of the study at 15 months (12 months after first biopsy).