Abstract
Immunosuppressant agents are essential in every transplant recipient’s care yet walking the fine line of over- or under-immunosuppression is a constant struggle for both patients and transplant providers alike. Optimization and personalization of immunosuppression has been limited by the need for non-invasive graft surveillance methods that are specific enough to identify organ injury in real time. With this in mind, we propose a pilot study protocol utilizing both donor derived cell free DNA (dd-cfDNA, gene expression profiling (GEP), and machine learning (iBox), called KidneyCare, to assess the feasibility and safety in reducing immunosuppressant exposure without increasing the risk of clinical rejection, graft injury, or allograft loss. Patients randomized to the immunominimization arm will be enrolled in one of two protocols designed to eliminate one immunosuppressant and optimize the dose of the Calcineurin Inhibitors (CNIs) using the KidneyCare platform. All patients will be maintained on dual therapy of either steroids and a low dose CNI, or mycophenolate mofetil (MMF) and low dose CNI. Their outcomes will be compared to patients who have their immunosuppressants managed using standard clinical assessment and treatment protocols to determine the impact of immuno-optimization on graft function, complications, and patient reported outcomes.
Highlights
Since 1980, cyclosporine has been administered to kidney transplant recipients (KTRs) to suppress immunologic reactions and limit allograft rejection, improving the success rate of organ transplantation
High doses of calcineurin inhibitors, such as tacrolimus, have been found to induce nephrotoxicity that contributes to allograft loss resulting from chronic allograft injury [4]
United Network for Organ Sharing (UNOS) data suggests up to 50% of patients are still on triple therapy two years post-transplant, with female patients more likely to be on triple therapy than male [7]
Summary
Since 1980, cyclosporine has been administered to kidney transplant recipients (KTRs) to suppress immunologic reactions and limit allograft rejection, improving the success rate of organ transplantation. There is significant concern that underimmunosuppression predisposes patients to the development of subclinical cellular rejection and the development of donor specific antibody (DSA), which impacts on term allograft survival [10] For this reason, the minimization of immunosuppressive agents has continued to be a controversial subject in the world of transplantation. Clinical assessment and routine laboratory tests (e.g., serum creatinine, proteinuria, CNI serum trough levels) do not precisely characterize the among of ongoing, subclinical, molecular injury of the organ or changes in the recipient’s immune system in response to changing immunosuppression These imprecise markers have been shown to be insensitive to early immunologic injury in the graft and significant findings are delayed until significant graft injury is already present [11]. Current measures of allograft function, such as creatinine, remain insensitive to early rejection resulting in delayed treatment that may increase the risk of acute and chronic allograft injury (CAI) and worsen the outcome of transplant recipients managed with immunosuppression optimization strategies. Clinicians have limited ability to detect injury early and
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