Donor-Derived Cell-free DNA for Personalized Immunosuppression in Renal Transplantation

Oellerich, Michael; Budde, Klemens; Osmanodja, Bilgin; Bornemann-Kolatzki, Kirsten; Beck, Julia; Schütz, Ekkehard; Walson, Philip D.

doi:10.1097/ftd.0000000000001023

Cited by 11 publications

(12 citation statements)

References 49 publications

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“…Though the optimal cutoff for dd-cfDNA for graft rejection continues to be investigated, dd-cfDNA offers utility as a non-invasive prognostic biomarker in posttransplant surveillance. 8,[18][19][20][21] The assessment of dd-cfDNA in repeat kidney transplant patients remains unclear. In our cohort, there were three such patients included.…”

Section: Discussionmentioning

confidence: 99%

“…Their results using dd‐cfDNA alone demonstrated a sensitivity of 49% and specificity of 86% at a cutoff of >1%, and reported an optimal cutoff of >0.77% with an AUC of 0.75. Though the optimal cutoff for dd‐cfDNA for graft rejection continues to be investigated, dd‐cfDNA offers utility as a non‐invasive prognostic biomarker in post‐transplant surveillance 8,18–21 …”

Section: Discussionmentioning

confidence: 99%

“…rejection, the median time to attain dd-cfDNA <1% post-rejection treatment was 8.5 days(3.0-19.5). In episodes of TCMR (n = 18), 8/18 (44.4%) had dd-cfDNA >1%, and after treatment 7 decreased to <1% at a median of 9 days (range[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. In episodes of AMR (n = 10), 9/10 had dd-cfDNA >1%, and after treatment only 1 decreased to <1% at 102 days.…”

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confidence: 99%

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Utilization of donor‐derived Cell‐Free DNA in pediatric kidney transplant recipients: A single center study

Ranch,

Fei,

Kincade

et al. 2023

Pediatric Transplantation

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High donor‐derived cell‐free DNA (dd‐cfDNA) levels indicate transplant allograft injury and can identify graft rejection in kidney transplant recipients. Here, we evaluated the use of dd‐cfDNA in pediatric kidney transplant rejection monitoring and treatment.MethodsForty‐two pediatric kidney transplant patients were enrolled between February 2020 and August 2021. Dd‐cfDNA was tested before and after biopsy/rejection treatment. There was a total of 61 allograft biopsies (44 for‐cause, 17 surveillance).ResultsGraft rejection was found in 35/61 biopsies. Rejection was more common in basiliximab induction compared to rATG (77.1% vs. 22.9%, p = .0121). Median dd‐cfDNA was higher in those with rejection (1.2% [0.34–3.12] vs. 0.24% [0.08–0.78], p < .0001). Dd‐cfDNA was highest in biopsies with AMR and mixed AMR/TCMR. In addition, dd‐cfDNA in basiliximab induction was higher compared to rATG (0.92% [0.27–1.8] vs. 0.26% [0.08–2], p = .0437). Median change in dd‐cfDNA after rejection treatment was −0.57% (−1.67 to 0.05). Median time to dd‐cfDNA <1% post‐rejection treatment was 8.5 days (3.0–19.5). Dd‐cfDNA in AMR was higher compared to TCMR or mixed rejection, and levels remained higher in AMR after treatment. In surveillance biopsies, 4/17 had rejection. Median dd‐cfDNA was not different in those with versus without rejection (0.48% vs. 0.28%, p = .2342). Those without rejection all had dd‐cfDNA <1%. In those with rejection, only one patient had dd‐cfDNA >1%, and all had TCMR.ConclusionsOur findings support dd‐cfDNA as a useful indicator of graft rejection and response to treatment. Additional studies are needed to determine the role of dd‐cfDNA in graft health surveillance.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Utilization of donor‐derived Cell‐Free DNA in pediatric kidney transplant recipients: A single center study

Ranch,

Fei,

Kincade

et al. 2023

Pediatric Transplantation

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“…However, the negative predictive value, which represented the probability of excluding rejection when the dd‐cfDNA test yielded a negative result, was high at 97% for dd‐cfDNA (cp/mL) and 90% for dd‐cfDNA (%). These findings suggested that a negative result on the dd‐cfDNA test provided strong reassurance that rejection was unlikely (Oellerich et al., 2021, 2023). When there is no active damage to the transplanted organ, the levels of dd‐cfDNA in the bloodstream were found to be less than 1% of total cfDNA.…”

Section: Main Textmentioning

confidence: 99%

Non‐invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview

Fernando,

Biswas,

Biswas

2024

Int J Immunogenetics

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Solid organ transplantation is a life‐saving intervention for individuals with end‐stage organ failure. Despite the effectiveness of immunosuppressive therapy, the risk of graft rejection persists in all viable transplants between individuals. The risk of rejection may vary depending on the degree of compatibility between the donor and recipient for both human leucocyte antigen (HLA) and non‐HLA gene‐encoded products. Monitoring the status of the allograft is a critical aspect of post‐transplant management, with invasive biopsies being the standard of care for detecting rejection. Non‐invasive biomarkers are increasingly being recognized as valuable tools for aiding in the detection of graft rejection, monitoring graft status and evaluating the efficacy of immunosuppressive therapy. Here, we focus on the importance of molecular biomarkers in solid organ transplantation and their potential role in clinical practice. Conventional molecular biomarkers used in transplantation include HLA typing, detection of anti‐HLA antibodies, killer cell immunoglobulin–like receptor genotypes, and anti‐MHC class 1–related chain A antibodies, which are important for assessing the compatibility of the donor and recipient. Emerging molecular biomarkers include the detection of donor‐derived cell‐free DNA, microRNAs (regulation of gene expression), exosomes (small vesicles secreted by cells), and kidney solid organ response test, in the recipient's blood for early signs of rejection. This review highlights the strengths and limitations of these molecular biomarkers and their potential role in improving transplant outcomes.

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“…It is currently used as a diagnostic test for antibody-mediated rejection (ABMR) and T-cell-mediated rejection (TCMR) [ 1 , 2 , 3 , 4 , 5 ]. Other suggested indications are guidance of immunosuppressive therapy, when no therapeutic drug monitoring (TDM) is available, for tapering of calcineurin inhibitors (CNI) or in clinically challenging dilemmas such as BK-nephropathy [ 6 , 7 ]. In those situations, detection of patients with overt or subclinical graft injury may support personalized immunosuppression.…”

Section: Introductionmentioning

confidence: 99%

Donor-Derived Cell-Free DNA for Kidney Allograft Surveillance after Conversion to Belatacept: Prospective Pilot Study

Osmanodja

Akifova

Oellerich

et al. 2023

JCM

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Donor-derived cell-free DNA (dd-cfDNA) is used as a biomarker for detection of antibody-mediated rejection (ABMR) and other forms of graft injury. Another potential indication is guidance of immunosuppressive therapy when no therapeutic drug monitoring is available. In such situations, detection of patients with overt or subclinical graft injury is important to personalize immunosuppression. We prospectively measured dd-cfDNA in 22 kidney transplant recipients (KTR) over a period of 6 months after conversion to belatacept for clinical indication and assessed routine clinical parameters. Patient and graft survival was 100% after 6 months, and eGFR remained stable (28.7 vs. 31.1 mL/min/1.73 m2, p = 0.60). Out of 22 patients, 2 (9%) developed biopsy-proven rejection—one episode of low-grade TCMR IA and one episode of caABMR. While both episodes were detected by increase in creatinine, the caABMR episode led to increase in absolute dd-cfDNA (168 copies/mL) above the cut-off of 50 copies/mL, while the TCMR episode did show slightly increased relative dd-cfDNA (0.85%) despite normal absolute dd-cfDNA (22 copies/mL). Dd-cfDNA did not differ before and after conversion in a subgroup of 12 KTR with previous calcineurin inhibitor therapy and no rejection (12.5 vs. 25.3 copies/mL, p = 0.34). In this subgroup, 3/12 (25%) patients showed increase of absolute dd-cfDNA above the prespecified cut-off (50 copies/mL) despite improving eGFR. Increase in dd-cfDNA after conversion to belatacept is common and could point towards subclinical allograft injury. To detect subclinical TCMR changes without vascular lesions, additional biomarkers or urinary dd-cfDNA should complement plasma dd-cfDNA. Resolving CNI toxicity is unlikely to be detected by decreased dd-cfDNA levels. In summary, the sole determination of dd-cfDNA has limited utility in the guidance of patients after late conversion to belatacept. Further studies should focus on patients undergoing early conversion and include protocol biopsies at least for patients with increased dd-cfDNA.

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Donor-Derived Cell-free DNA for Personalized Immunosuppression in Renal Transplantation

Cited by 11 publications

References 49 publications

Utilization of donor‐derived Cell‐Free DNA in pediatric kidney transplant recipients: A single center study

Utilization of donor‐derived Cell‐Free DNA in pediatric kidney transplant recipients: A single center study

Non‐invasive molecular biomarkers for monitoring solid organ transplantation: A comprehensive overview

Donor-Derived Cell-Free DNA for Kidney Allograft Surveillance after Conversion to Belatacept: Prospective Pilot Study

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