The development of immunosuppressive agents decades ago significantly increased short-term survival in solid organ transplant. But improvements in long-term outcomes have lagged.

“Among heart transplant recipients, the 1-year survival rate exceeds 90% nationwide,” says Dr. Khush. “But patients experience high rates of immunosuppression-related complications, including severe renal dysfunction, diabetes, and cancer. And cardiac allograft vasculopathy, a leading cause of chronic graft failure, affects nearly half of patients 10 years after heart transplant.”

With similar problems plaguing other types of SOT, it's clear that the one-size-fits-all immunosuppression model needs improvement. Moreover, such improvement requires better post-transplant monitoring and diagnostics.

Molecular biomarkers for immune monitoring

Traditional transplant surveillance has focused on early detection of complications that can affect graft function and rejection. Typical surveillance methods include organ-specific blood tests, imaging, and functional assessments. Biopsies are also often part of routine monitoring, despite their clinical limitations, risks, cost, and inconvenience to patients.

New molecular biomarkers enhance monitoring with their ability to predict acute rejection. Based on this personalized risk estimate, doctors can more precisely dose each patient’s immunosuppression, which reduces adverse effects.

Donor-specific anti-HLA antibody testing is the most widely used biomarker assay and has become the standard of care across SOT. Other emerging biomarker assays include:

• Donor-derived cell-free DNA: This test measures donor organ DNA in the transplant recipient’s blood or urine. The release of DNA fragments from the transplanted organ indicates allograft injury, although not the type of injury.
• Gene expression profiling: This test quantifies the expression of multiple genes involved in the alloimmune response. The International Society for Heart and Lung Transplantation (ISHLT) recommends gene expression profiling as an alternative to endomyocardial biopsy for routine surveillance in low-risk heart transplant recipients.

Biomarker tests can also be used together to enhance post-transplant surveillance. “We recently published an article showing the complementary value of testing with both donor-derived cell-free DNA and gene expression profiling,” says Dr. Khush. “Dual testing improved the detection of patients at risk of acute cellular rejection after heart transplant. It also decreased biopsy rates over time.”

Precision diagnostics in transplantation

Biopsy protocols for diagnosing the underlying cause of allograft injury have evolved to include multimodal data. Despite these refinements, their accuracy is limited. New tools are poised to further enhance the diagnostic capability of biopsies.

A few notable examples of innovation in this area include:

• Computational pathology: AI-based models are still in developmental stages but have the potential to automate histological analysis of diagnostic biopsies, reducing analysis time and improving reproducibility. In heart transplants, early studies of these models demonstrate their ability to define tissue structures and quantify lymphocytic infiltration and, therefore, inflammation.
• Multigene expression profiling: This technology detects molecular signs of organ injury and provides more accurate insights into whether the cause is rejection or another process. Diagnostic gene expression profiling has the potential to support personalized treatment planning. However, its use is limited due to analytical challenges and the need for an additional biopsy sample. Current research aims to enable molecular analysis of the same biopsy core used for histological assessment and reduce the time and cost of analysis.

“We are at the forefront of precision diagnostics,” says Dr. Khush. “As these tools expand into clinical use, they will help doctors counsel transplant patients about their prognosis and apply targeted treatments.”

Learn more about heart transplantation at Stanford Health Care.