Dr. Michael Marvin is the Chair of the Department of Transplantation and Liver Surgery at Geisinger Health System and a Professor of Surgery at Geisinger Commonwealth School of Medicine. He specializes in liver and kidney transplants, as well as minimally-invasive living donor nephrectomy. He has extensive experience in the management of post-transplant kidney recipients and the use of novel biomarkers to individualize their care.

Dr. Marvin spoke during a November 2023 webinar, “Using Gene Expression Profile Biomarkers as an Immunosuppression Guide in Post-Transplant Care.” Along with Dr. John Friedewald and Dr. Ram Pedi, he addressed one of the most challenging questions facing transplant doctors. How much immunosuppression is enough to prevent rejection?

Study Overview: Gene Expression Profile Biomarkers

Gene expression profile biomarkers are a noninvasive way to rule out subclinical rejection in posttransplant patients. Biomarker tests can determine whether the patient is adequately immunosuppressed — without the need for surveillance biopsies. The results of these tests help physicians guide management of immunosuppression and determine if a biopsy is warranted.

Dr. Marvin’s clinical practice is informed in part by a study of TruGraf, a gene expression profile biomarker test. The study used TruGraf results to guide immunosuppression reduction in low-risk transplant patients. When the result was TX (transplant excellent, no evidence of subclinical rejection), researchers dropped immunosuppression doses. When the test returned a non-TX (possible subclinical rejection), the levels would remain unchanged. By month 12, the Mycophenolate and Tacrolimus doses were significantly lower in the study group than in the control group…?without evidence of rejection episodes?

After reviewing the results of this study, Dr. Marvin’s team embarked on a practice of monitoring posttransplant patients with both Trugraf and traditional donor-derived cell-free DNA (dd-cfDNA) tests. They found these tests extremely useful in helping to manage the increasing incidence of viral infection (e.g. CMV/BK) and adverse drug reactions (e.g. tremors) occurring in their transplant recipients. When a patient developed these complications, and immunosuppression modification was needed, a Trugraf test would be ordered to ensure that the modifications to the drug regimen would not lead to unrecognized subclinical rejection.

TruGraf and dd-cfDNA tests proved to have different but complementary insights. The dd-cfDNA tests are better at detecting active injury and antibody-mediated rejection (AMR) while TruGraf is more effective at identifying immune quiescence and acute cellular rejection (ACR). The tests work best in combination, but TruGraf is a better option for immunosuppression titration in the setting of viral infection and/or adverse drug effects.

Dr. Marvin believes that some clinicians who struggle with the TruGraf test may not be using it optimally. It is critical to understand that while the negative predictive value of a Tx result is 85-90%, the positive predictive value of a non-Tx result is only around 50-60%…..meaning a non-Tx result does not necessarily indicate a need for biopsy. It is an indication of the need for closer monitoring and possibly repeat testing. A biopsy might ultimately be indicated, but a single, isolated non-Tx, in the absence of an elevated dd-cfDNA or other indicators of rejection, is not always warranted.

When the patient gets a non-TX result, it’s important to look at other factors:

Are donor-specific antibodies (DSA) present?
Is the patient taking their medicine correctly?
An invasive biopsy should only come after physicians have considered other possibilities.

Results and Implications for Transplant Recipients

In the first 2 years following a kidney transplant, ~25% of patients experience subclinical rejection. When physicians can detect this issue early on, it’s easier to take corrective action. Since dd-cfDNA and gene expression biomarker testing are complimentary at identifying different types of rejection, they can be used in combination to improve long-term patient outcomes. Dr. Marvin is using this method in his clinical practice with encouraging results.

Patient Case #1

This patient is a 77-year-old female with polycystic kidney disease. She had a kidney transplant and was initially on a standard FK/MPA protocol, with steroids only for rATG induction. When she developed tremors, she was converted from a rapid-acting tacrolimus product to a long-acting version. The tremors didn’t improve, so the patient was changed to belatacept with mycophenolate mofetil (MMF). After she developed BK and CMV, the team switched to sirolimus.

While all this was happening, the patient was monitored with dd-cfDNA and TruGraf tests. Using the results as guardrails, she was able to be converted to a low-dose monotherapy cyclosporine (CsA)regimen. Without biomarker testing, this course of action would have been improbable. Reducing immunosuppression resolved the BK and CMV, and the patient sustained creatinine levels of 0.7 and 0.8. Today, she is 5 years post transplant, and her creatinine levels are holding steady at 0.8.

Patient Case #2

This patient is a 69-year-old woman with a kidney transplant. After a biopsy indicated that her kidney was less than perfect, she was transitioned to belatacept early on. A TruGraf test returned a non-TX result at the 8-month mark, but dd-cfDNA results were normal. In month 10, however, the dd-cfDNA results spiked.

A biopsy was ordered, which detected borderline T cell-mediated rejection. In response, the team increased the patient’s CellCept dose and administered a small steroid pulse. By month 12, both the dd-cfDNA and TruGraf results were back to normal.

Throughout this period, the patient’s creatinine levels remained within a normal range — which reinforces the importance of biomarker testing. With dd-cfDNA tests alone, doctors wouldn’t have detected and resolved the rejection so early.

Dr. Marvin’s experience indicates that biomarkers have the potential to significantly improve post transplant care. Used with dd-cfDNA tests, they can help detect subclinical rejection, reduce side effects, and find a safe, effective immunosuppression level.

Future Directions and Importance of Combined Testing

Combined testing has the potential to improve post transplant care. First, however, healthcare professionals must learn to use biomarker and dd-cfDNA tests in an optimized and productive way. Responsible usage may help convince insurance companies to cover testing costs, which are roughly $60,000 per patient, per year. Currently, Medicare isn’t always willing to approve the tests, due in part to past overuse of dd-cfDNA monitoring.

Dr. Marvin believes that education is the key to successful biomarker integration. Transplant physicians need training to understand:

When to order tests
How to order tests
How to respond to the results

With this knowledge, doctors can reduce unnecessary testing and use combined biomarker and dd-cfDNA monitoring to improve patient care. The highly accurate results help refine immunosuppression levels, reduce invasive procedures, and create better long-term patient outcomes.

Transplant Genomics aims to improve transplant outcomes for recipients through noninvasive treatment options. Learn more today.