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Clinical Rationale for a Routine Testing Schedule Using Donor-Derived Cell-Free DNA After Kidney Transplantation.

ABSTRACT: Kidney transplant recipients require meticulous clinical and laboratory surveillance to monitor allograft health. Conventional biomarkers, including serum creatinine and proteinuria, are lagging indicators of allograft injury, often rising only after significant and potentially irreversible damage has occurred. Immunosuppressive medication levels can be followed, but their utility is largely limited to guiding dosing changes or assessing adherence. Kidney biopsy, the criterion standard for the diagnosis and characterization of injury, is invasive and thus poorly suited for frequent surveillance. Donor-derived cell-free DNA (dd-cfDNA) is a sensitive, noninvasive, leading indicator of allograft injury, which offers the opportunity for expedited intervention and can improve long-term allograft outcomes. This article describes the clinical rationale for a routine testing schedule utilizing dd-cfDNA surveillance at months 1, 2, 3, 4, 6, 9, and 12 during the first year following kidney transplantation and quarterly thereafter. These time points coincide with major immunologic transition points after transplantation and provide clinicians with molecular information to help inform decision making.

SUBMITTER: Pai A

PROVIDER: S-EPMC8259349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from a large number of published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. Dd-cfDNA indicates graft cell death without being rejection specific. It can be determined in plasma through droplet digital PCR using preselected SNPs or next generation sequencing. Changes in recipient cfDNA (e.g., by infection) can affect the results of dd-cfDNA fractional determination. This limitation can be overcome using absolute dd-cfDNA quantification. The combination of fractional and absolute determination including total cfDNA is recommended for meaningful interpretation of the results. The value proposition for the patient includes earlier transplant injury detection and intervention, less full blown rejection risk, an alternative to invasive biopsies, and personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would result from fewer biopsies as a result of the tests' high negative predictive value, fewer re-transplantations, and less organ failure with return to dialysis. A pathway to implementation and metrics is suggested to measure the effectiveness of dd-cfDNA testing.

Project description:Background: Donor-derived cell-free DNA (ddcfDNA) has been suggested as an indicator of allograft injury in adult and pediatric kidney transplantation (KTx). However, the dynamics of ddcfDNA in pediatric KTx have not been investigated. In addition, it has not been demonstrated whether donor-recipient (D/R) size mismatch affect ddcfDNA level. Methods: Pediatric KTx recipients with a single donor kidney were enrolled and followed up for 1 year. ddcfDNA, calculated as a fraction (%) in the recipient plasma, was examined longitudinally within 3 months post-transplant. D/R size mismatch degree was described as D/R height ratio. The 33rd percentile of D/R height ratio (0.70) was used as the cut-off to divide the patients into low donor-recipient height ratio group (<0.70) and high donor-recipient height ratio group (≥0.70). The dynamics of ddcfDNA were analyzed and the impact factors were explored. Stable ddcfDNA was defined as the first lowest ddcfDNA. ddcfDNA flare-up was defined as a remarkable elevation by a proportion of >30% from stable value with a peak value >1% during elevation. Results: Twenty-one clinically stable recipients were enrolled. The median D/R height ratio was 0.83 (0.62-0.88). It took a median of 8 days for ddcfDNA to drop from day 1 and reach a stable value of 0.67% (0.46-0.73%). Nevertheless, 61.5% patients presented ddcfDNA>1% at day 30. Besides, 81.0% (17/21) of patients experienced elevated ddcfDNA and 47.6% (10/21) met the standard of ddcfDNA flare-up. Donor-recipient height ratio was an independent risk factor for ddcfDNA flare-up (odds ratio = 0.469 per 0.1, 95% CI 0.237-0.925, p = 0.029) and low donor-recipient height ratio (<0.70) was found to increase the risk of flare-up occurrence (odds ratio = 15.00, 95% CI 1.342-167.638, p = 0.028). Conclusions: ddcfDNA rebounds in many stable pediatric KTx recipients without rejection. This may be induced by significant D/R size mismatch and may affect its diagnostic performance at the early phase after pediatric KTx in children.

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Clinical Rationale for a Routine Testing Schedule Using Donor-Derived Cell-Free DNA After Kidney Transplantation.

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