Precision Medicine in Kidney Transplantation: Are We There yet?

Transplant Institute Update | June 2025

Contributed by: Krishna Balabhadrapatruni, MD

Krishna Balabhadrapatruni, MD

Organ transplantation has emerged as one of the revolutionary advancements in the field of medicine since the first kidney transplant in 1950s. Dramatic improvement in short-term graft outcomes was achieved since the introduction of calcineurin inhibitors (CNI) in early 1990s resulting in >90% 1-year survival rates but long-term survival remained lagging with 5- and 10- year graft survival rates at 77% and 49% respectively (OPTN, 2019). A key reason for this shortcoming is thought to be a lack of individual immunologic risk stratification and thus individualized immunosuppressive therapy.

Transplant medicine has operated on a cohort (‘one-size-fits-all’) approach for quite some time. Standard induction and maintenance immunosuppressive therapy protocols were adopted with considerable inter- and intra-center variability dependent on various factors. CNI doses were titrated to meet a pre-specified target range (6 to 10 ng/ml) while other immunosuppressive agents were titrated only upon identifying toxicity features. Transplant recipients, requiring ‘lifelong’ immunosuppressive therapy, are increasingly at risk for developing uncommon infections, bone marrow suppression and malignancies. There appears to be a lack of a ‘clinical yardstick’ by which the degree of immunosuppression can be measured.

With the advances in molecular medicine in the past decade or so, much focus and emphasis has been on precision medicine in an effort to identify safe and effective treatment strategies based on genetics and environment that are unique to individuals. Histocompatibility remains the cornerstone of success in kidney transplantation, however, donor-to-recipient matching is always a compromise between ‘waiting time’ and availability of a suitable donor kidney. The advent of high resolution HLA typing and identification of unacceptable antigens by single bead testing allows for precise risk assessment pre-transplantation, thus eliminating risk of early graft failure due to preformed HLA antibodies. There is growing evidence to suggest donor-to-recipient incompatibilities, outside of HLA regions, play a crucial role in rejection as well. More emphasis is being placed on epitope matching and identifying eplet mismatch load with calls to potentially incorporate these metrics in organ allocation algorithms.  

Several biomarkers have been studied in transplant recipients to determine risk of rejection and graft dysfunction, including but not limited to,  IFN-γ, IL-2, CXCL9, TIM-3, urinary cell mRNA, donor-derived- cell free DNA (dd-cfDNA). Of these, the urinary cell m-RNA profiling and dd-cfDNA have gained much attention. Urinary cell mRNA profiling (ExoTru TM by Thermo Fisher; currently in FDA approval process), has been shown to be predictive of acute rejection with change in levels several weeks prior to the event. A four mRNA signature performed well in distinguishing biopsies with rejection or inflammation versus without, predicting adverse graft outcomes in 5-year follow up. A 6-gene signature was able to distinguish cell-mediated and antibody-mediated rejection.

The use of dd-cfDNA has been adopted by several centers over the past few years, current popular commercially available options include Allosure® (CareDx) and Prospera™ (Natera). In the DART trial (JASN, 2017), dd-cfDNA (Allosure®) utilizing 1% cut-off threshold, had 95% negative predictive value (median dd-cfDNA 0.21%) for ruling out rejection, high 93% specificity for detecting active rejection (median 1.6%), and 85% positive predictive value for active antibody-mediated rejection (median dd-cfDNA 2.9%). In addition to acting as a noninvasive marker of potential rejection, dd-cfDNA may be utilized as a marker of degree of immunosuppression.

Recent addition to precision diagnostics in kidney transplantation is the potential role of Molecular Microscopic Diagnostic System (MMDx), which utilizes genome-wide microarrays to measure transcript expression, employing machine learning algorithms to generate a report of presence or absence of rejection, identify subclinical rejection and parenchymal injury to assess graft outcomes. This tool can be deployed as a complement to standard histopathologic evaluation especially in cases with ambiguous results. MMDx has not been FDA approved, yet.

Studies on precision therapeutics in kidney transplantation largely focus on CYP3A4 and CYP3A5 polymorphisms that influence tacrolimus metabolism. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines suggest that CYP3A5 extensive metabolizers or intermediate metabolizers (CYP3A5 expressers) need higher tacrolimus initiation dose, while CYP3A5 non-expressers (poor metabolizers) require much lower doses. Candidate gene polymorphisms for other maintenance immunosuppressants have also been studied such as hypoxanthine-guanine phosphoribosyl-transferase (HGPT) deficiency for mycophenolic acid, thiopurine methyltransferase (TPMT) for azathioprine.

Lastly, one would be remiss if precision medicine techniques are not deployed in the right context of demographic, highlighting the importance of population health implementation strategies to allow for appropriate and effective allocation of resources in chronic disease conditions such as kidney failure and transplantation.