Kidney, heart transplant ‘years ahead of’ LT in development, implementation of biomarkers
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Although the development and use of biomarkers in liver transplantation has progressed in recent years, challenges and limitations remain, according to presenters at the American Transplant Congress 2022.
Thomas D. Schiano, MD, professor of medicine and liver diseases at Mount Sinai in New York, told attendees that among transplant patients, biomarkers should monitor short- and long-term graft function, predict acute and chronic disease development, assess donor organ quality or monitor response to therapeutic intervention. Further, biomarkers should have external validation.
“This is the key here,” Schiano said. “They need external validation. We need more of this and allowance for repetitive assessment over time. Kidney and heart transplant are years ahead of liver transplant physicians in the development and implement implementation of biomarkers.”
Biomarker advantages and limitations
According to Schiano, recent and ongoing studies have assessed gene expression profiles and donor-derived cell-free DNA (dd-cfDNA), which have shown promising results in guiding immunosuppression management, particularly when hepatitis C infection is absent.
Thus far, dd-cfDNA has been extensively studied as a biomarker for rejection in renal and cardiac transplantation and as part of clinical practice, he said. The biomarker it is not specific to a particular disease or etiology and does increase with a rise in liver chemistry tests, which has been a limitation.
“In the absence of hepatitis C infection, however, an increase in donor-derived cell-free DNA is more pertinent to identify allograft dysfunction,” Schiano said. “A recent, very exciting study shows that a steadily increasing proportion of donor-derived cell-free DNA precedes an elevation of liver chemistry tests in acute cellular rejection and then decreases following resolution of the treatment of acute cellular rejection.”
Other biomarkers being studied for LT include microRNAs (miRNAs), which are organ-specific, non-coding single-strand RNA molecules.
As promising as these biomarkers may be, they all “have advantages and limitations,” according to Schiano. Donor-derived cell free DNA has a short life that offers real time indication of liver damage, and miRNAs are liver- or immune cell-specific, making combination of different miRNAs helpful.
However, research using machine learning in post-LT is underway and will help personalize treatment strategies.
“The reality of precision medicine and the day-to-day management of post liver transplant patients is fast approaching,” Schiano said.
Biomarkers ‘need to be realistic’
“Probably the best thing that happened in liver transplant was the eradication of hepatitis C,” Josh Levitsky, MD, MS, professor of medicine and surgery at Northwestern University Feinberg School of Medicine in Chicago, said during his presentation. “I think this was a big reason why liver has been behind heart and kidney and other organs — because we were focused on hepatitis C. Now that's not really a problem anymore. We can really refocus on having biomarkers that are nonviral-related or viral reactivation and can now be more applicable to the broader population.”
According to Levitsky, the field has moved toward more clinically applicable and usable biomarkers in clinical practice, which can be sampled from blood.
Current tests that look at the absence of subclinical inflammation for immunosuppression minimization include liver enzymes, donor-specific antibody and Fibroscan, while blood-based biomarkers such as mRNA, macroRNA, dd-cfDNA, cytokines and proteoforms are being studied.
“We're trying to enhance specificity rejection monitoring, but these tests are coming — hopefully very soon to clinical practice — alongside kidney and heart transplant, where they're actually being used to manage patients,” Levitsky said. “I do think that biomarkers are certainly cool, but they need to be realistic. The liver field has progressed a lot in the last 5 to 7 years since hepatitis C eradication, and I think we are getting closer to other organs.”
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Levitsky J, et al. Biomarkers seem really cool, but are they for real? The prospect of using the most promising candidate biomarkers in liver transplant practice. Presented at: American Transplant Congress; June 4-8, 2022; Boston (hybrid meeting).
Schiano T, et al. Biomarkers seem really cool, but are they for real? The prospect of using the most promising candidate biomarkers in liver transplant practice. Presented at: American Transplant Congress; June 4-8, 2022; Boston (hybrid meeting).
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