TRANSPLANT MONITORING
the technology providers and kind contributions from Southmead Hospital Charity. This proof-of-concept study would generate real-world data for future clinical validation and contribute to future NICE evaluation processes.
cfDNA: an emerging biomarker for allograft rejection The path from research to clinical application of donor-derived cfDNA surveillance is surprisingly long. Although nucleic acids were first observed in human plasma in 1948 by Mandel and Matais, it wasn’t until 1998 when Lo et al. reported the presence of donor-specific cfDNA blood plasma of kidney and liver transplant that cfDNA monitoring in solid organ transplant patients became a possibility.8,9
Analysis of cfDNA from the
The NHSBT Histocompatibility and Immunogenetics (H&I) laboratory in Bristol supports the local renal transplant unit with services including human leukocyte antigen (HLA) typing, HLA antibody screening and crossmatching, and donor typing.
than existing markers.1,3,4 An increasing
number of studies have investigated the clinical validity of tracking dd-cfDNA levels in plasma to identify allograft injury and active rejection.4-6
NHSBT laboratory framework and clinical challenge Dr Sarinder Day is the lead clinical scientist in immunogenetics at the NHS Blood and Transplant (NHSBT) Histocompatibility and Immunogenetics (H&I) laboratory in Bristol. The immunogenetics laboratory supports the local renal transplant unit by providing 24/7 H&I services including human leucocyte antigen (HLA) typing both for patients and donors, HLA antibody screening and crossmatching, and local deceased donor typing for national organ allocation. Unacceptable antigens are reported to the national registry to guide donor selection. A matching run algorithm considers HLA compatibility and antibody profiles to
minimise rejection risk. Crossmatching is performed by flow cytometry to assess donor-recipient compatibility. Despite compatibility, some patients can still go on to develop de novo antibodies and have rejection episodes, and this is where dd-cfDNA testing may inform and allow early intervention to prevent serious kidney damage, increasing the longevity of the allograft. To investigate the utility of cfDNA as a non-invasive alternative to biopsy, particularly in detecting early signs of graft dysfunction in kidney transplant recipients, a cfDNA pilot study involving 240 cfDNA tests is taking place at North Bristol NHS Trust. The study is being led by renal consultants Dr Rommel Ravanan and Dr Ailish Nimmo, along with renal registrar Dr Krishnappan Ramanathan and transplant nurse specialist Claire Adams, supported by the H&I laboratory collaborators at North Bristol. This evaluation has been possible due to contribution of testing kits by
bloodstream has been widely embraced as a minimally invasive method of assessing a patient’s physiological state. Although historically linked to cancer diagnostics, studies have also demonstrated elevated cfDNA levels in systemic lupus erythematosus and rheumatoid arthritis. This highlights that circulating cell-free DNA (cfDNA) is rapidly transitioning from research laboratories to an important tool in clinical decision-making.10 There has been a gradual shift globally in transplant monitoring methods, with standardised dd-cfDNA surveillance being introduced into clinical use to monitor kidney transplant rejection in the US.11
A working group for the European
Sarinder Day shares the opinion that transplant physicians would benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated
46
Society of Organ Transplantation met in early 2024 to review literature of molecular biomarkers for kidney transplant rejection and agree screening and diagnostic guidelines. Within these guidelines they make a moderately confident recommendation to clinicians to measure plasma dd-cfDNA in patients with acute graft dysfunction to exclude the presence of rejection antibodies.12 Whilst the utility of dd-cfDNA as a marker of rejection has been firmly established in heart, kidney, liver, lung, and other transplants it has yet to be established in UK clinical settings. Potential benefits and drivers behind the NBT pilot study for kidney transplant patients include logistics of travel and disruption to patients’ lives and routine. Invasive biopsies could be replaced by a simple blood test, detecting graft failure earlier, and facilitating personalised immunosuppression. Donor-derived cfDNA has been particularly beneficial to heart transplantation patients, where there are no blood tests like serum creatinine available and biopsies are routinely performed to monitor rejection.
OCTOBER 2025
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