Precision Transplant Medicine: Biomarkers to the Rescue

Abstract

The concept that individuals with the same disease and a similar clinical presentation may have very different outcomes and need very different therapies is not novel. With the development of many innovative tools derived from the omics technologies, transplant medicine is slowly entering the era of precision medicine. Biomarkers are the cornerstone of precision medicine, which aims to integrate biomarkers with traditional clinical information and tailor medical care to achieve the best outcome for an individual patient. Here, we discuss the basic concepts of precision medicine and biomarkers, with a specific focus on progress in renal transplantation. We delineate the different types of biomarkers and provide a general assessment of the current applications and shortcomings of previously proposed biomarkers. We also outline the potential of precision medicine in transplantation. Moving toward precision medicine in the field of transplantation will require transplant physicians to embrace the increased complexity and expanded decision algorithms and therapeutic options that are associated with improved disease nosology.

Keywords: acute rejection; chronic allograft failure; chronic graft deterioration; kidney transplantation; transplant outcomes.

Figure 1.

The shortcomings of currently used biomarkers in transplant medicine.

Figure 2.

Overview of biomarker subtypes for precision transplant medicine.

Figure 3.

Time dependency of the different types of biomarkers for precision medicine. Before any disease activity is present, risk/susceptibility biomarkers will facilitate the identification of high-risk patients who require closer follow-up examinations, which are typically performed using noninvasive diagnostic biomarkers. These biomarkers ideally also detect subclinical disease activity before clinical signs or irreversible injury become evident. After a disease process is diagnosed or its activity is assessed, a prognostic biomarker estimates the effect of the disease and the chance of spontaneous resolution versus that of irreversible injury and eventually, graft failure. A prognostic biomarker should be able to identify those patients who need treatment and those patients who will have spontaneous disease resolution or a good prognosis in the absence of therapy. If a patient with disease would have a poor outcome according to the prognostic biomarker, the search for an appropriate therapy can begin. Ideally, this therapy is not solely on the basis of the diagnosis and prognosis of the disease but also, on the basis of predictive biomarkers that predict which treatment has the highest chance of success in reversing the outcome. Disease activity should be assessed over time using monitoring biomarkers, including after therapy cessation. In addition, there are crucial differences in the nature of biomarkers. If repeated biomarker assessment is necessary (e.g., as with diagnostic biomarkers for subclinical disease, safety/pharmacodynamic/response biomarkers, and monitoring biomarkers), ideally, noninvasive tests should be developed and used. For biomarkers that are used for treatment decisions (e.g., whether to start treatment and the type of treatment), such as some diagnostic, prognostic, and predictive biomarkers, noninvasiveness is a plus but is not essential. Important treatment decisions are typically not very repetitive and can be on the basis of invasive biomarker assessments. Thus, invasive biomarkers have very different clinical applications than noninvasive biomarkers.

Figure 4.

Overview of the diagnostic performance (sensitivity and specificity) of the noninvasive diagnostic biomarkers for acute rejection. Modified from ref. , with permission.

Figure 5.

Ideal pipeline for developing clinically usable and useful biomarkers in renal transplantation. The clinical assessment of medical devices is on the basis of completely different methods from those applied to medicinal products; consequently, new tools might be marketed after a very limited validation process, which may alter the capacity of the medical device to be reimbursed by National Health Insurance, with reimbursement being guided on the basis of assessments of the actual benefit and the added clinical value. Therefore, a strong multistep validation is required to avoid concerns that new diagnostic tests may increase health care expenditures and skepticism about their benefits in terms of improving clinical management.