Reduction in Maintenance Immunosuppression in Kidney Transplant Recipients With Stable Donor-Derived Cell-Free DNA Measurements: A Case Series

Lum, Erik L.; Towns, Arta; Basuli, Debargha; Pham, Phuong‐Thu T.; Sarkar, Mrinalini; Bunnapradist, Suphamai

doi:10.1016/j.transproceed.2022.12.003

Cited by 5 publications

(4 citation statements)

References 17 publications

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“…Timely, non-invasive detection of increased dd-cfDNA levels in SOT recipients could reduce unnecessary biopsies [41][42][43][44] and allow clinicians to promptly modify immunosuppression. [45][46][47] The dd-cfDNA assay evaluated here is a targeted NGS assay utilising 202 SNPs throughout the genome to quantify dd-cfDNA from transplant recipient blood. This verification study was conducted by laboratory end users, including performing the streamlined protocol compatible with clinical laboratory practices and running the automatic analysis software to quantify dd-cfDNA without genotyping, 48 with turnaround time of under 24 h from cfDNA sample to result, 38 enabling efficient posttransplant surveillance.…”

Section: Discussionmentioning

confidence: 99%

“…In SOT recipients, dd‐cfDNA is an effective, minimally‐invasive biomarker of transplant allograft injury that enables frequent, safe and quantitative surveillance. Timely, non‐invasive detection of increased dd‐cfDNA levels in SOT recipients could reduce unnecessary biopsies 41–44 and allow clinicians to promptly modify immunosuppression 45–47 …”

Section: Discussionunclassified

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Multi‐centre analytical performance verification of an IVD assay to quantify donor‐derived cell‐free DNA in solid organ transplant recipients

Casas,

Tangprasertchai,

Oikonomaki

et al. 2024

HLA

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Donor‐derived cell‐free DNA (dd‐cfDNA) has been widely studied as biomarker for non‐invasive allograft rejection monitoring. Earlier rejection detection enables more prompt diagnosis and intervention, ultimately improving patient treatment and outcomes. This multi‐centre study aims to verify analytical performance of a next‐generation sequencing‐based dd‐cfDNA assay at end‐user environments. Three independent laboratories received the same experimental design and 16 blinded samples to perform cfDNA extraction and the dd‐cfDNA assay workflow. dd‐cfDNA results were compared between sites and against manufacturer validation to evaluate concordance, reproducibility, repeatability and verify analytical performance. A total of 247 sample libraries were generated across 18 runs, with completion time of <24 h. A 96.0% first pass rate highlighted minimal failures. Overall observed versus expected dd‐cfDNA results demonstrated good concordance and a strong positive correlation with linear least squares regression r2 = 0.9989, and high repeatability and reproducibility within and between sites, respectively (p > 0.05). Manufacturer validation established limit of blank 0.18%, limit of detection 0.23% and limit of quantification 0.23%, and results from independent sites verified those limits. Parallel analyses illustrated no significant difference (p = 0.951) between dd‐cfDNA results with or without recipient genotype. The dd‐cfDNA assay evaluated here has been verified as a reliable method for efficient, reproducible dd‐cfDNA quantification in plasma from solid organ transplant recipients without requiring genotyping. Implementation of onsite dd‐cfDNA testing at clinical laboratories could facilitate earlier detection of allograft injury, bearing great potential for patient care.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionunclassified

Multi‐centre analytical performance verification of an IVD assay to quantify donor‐derived cell‐free DNA in solid organ transplant recipients

Casas,

Tangprasertchai,

Oikonomaki

et al. 2024

HLA

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“…In renal transplant recipients who developed de novo donor specific antibodies (dnDSAs), a rise in dd-cfDNA > 0.5% occurred a median of 91 days preceding detection of dnDSAs [16]. The first large multicenter trials aiming to compare dd-cfDNA measurements with the molecular phenotype of kidney transplant biopsies [17], as well as short patient series trying to enhance the use of dd-cfDNA information to guide clinical practice and immunomodulation decisions [18] have recently been published, while additional interventional studies are in progress [19].…”

Section: Introductionmentioning

confidence: 99%

Assessment of Donor Derived Cell Free DNA (dd-cfDNA) at Surveillance and at Clinical Suspicion of Acute Rejection in Renal Transplantation

Mantios,

Filiopoulos,

Constantoulakis

et al. 2023

Transpl Int

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In our prospective, unicenter cohort study, we collected blood samples from 30 newly kidney transplanted patients, at month 1, 2, 3, and 5 for dd-cfDNA analysis, along with creatinine/eGFR and DSA monitoring, and from 32 patients who underwent an indication biopsy and whose dd-cfDNA levels were measured at the time of biopsy and 1 month afterwards. Fourteen of 32 (43.8%) patients in the biopsy group were diagnosed with TCMR and 5 of 32 (15.6%) with ABMR. Dd-cfDNA proved to be better than creatinine in diagnosing rejection from non-rejection in patients who were biopsied. When a dd-cfDNA threshold of 0.5% was chosen, sensitivity was 73.7% and specificity was 92.3% (AUC: 0.804, 0.646–0.961). In rejection patients, levels of dd-cfDNA prior to biopsy (0.94%, 0.3–2.0) decreased substantially after initiation of treatment with median returning to baseline already at 1 month (0.33%, 0.21–0.51, p = 0.0036). In the surveillance group, high levels of dd-cfDNA (>0.5%) from second month post-transplantation were correlated with non-increasing eGFR 1 year post-transplantation. The study used AlloSeq kit for kidney transplant surveillance for first time and confirmed dd-cfDNA’s ability to detect rejection and monitor treatment, as well as to predict worse long-term outcomes regarding eGFR.

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“…We felt that using dd-cfDNA to help inform IST reduction would allow for a low-risk trial design. Recently, a small case series successfully explored the use of dd-cfDNA as part of tailored IST reduction in a limited number of stable patients (n = 5), 17 where each patient received a tailored intervention including different kinds of IST regimens. In contrast, our study incorporated a larger cohort of patients (n = 21) who underwent a standardized intervention of one kind of IST.…”

mentioning

confidence: 99%

Use of Donor-derived Cell-free DNA to Inform Tapering of Immunosuppression Therapy in Kidney Transplant Recipients: An Observational Study

Osuchukwu,

Trevino,

McCormick

et al. 2024

Transplantation Direct

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Background. Immunosuppression therapy (IST) is required for allograft survival but can cause significant adverse effects. Donor-derived cell-free DNA (dd-cfDNA) is a validated noninvasive biomarker for active rejection in kidney transplant (KTx). Evidence supporting dd-cfDNA testing use in IST management is limited. Methods. In this single-center observational study, dd-cfDNA testing was performed in 21 KTx patients considered good candidates for mycophenolic acid (MPA) reduction. Patients with dd-cfDNA <1% at the first visit (enrollment) had their MPA dosage reduced; those with dd-cfDNA ≥1% had their MPA dosage maintained. Patients were monitored with dd-cfDNA for 6 additional visits. Results. Of 21 patients enrolled in the study, 17 were considered low risk for rejection by dd-cfDNA and underwent MPA reduction; 4 patients were considered high risk for rejection by dd-cfDNA and had their initial MPA dosage maintained. Of the 4 patients considered high risk for rejection by dd-cfDNA, 1 experienced chronic allograft nephropathy and graft loss, and another received an indication biopsy that showed no evidence of rejection. Of the 17 patients considered low risk for rejection by dd-cfDNA, none experienced allograft rejection. dd-cfDNA was used for surveillance in a 6-mo period following MPA reduction; no untoward results were noted. Conclusions. This proof-of-concept study reports the use of dd-cfDNA to directly inform IST management in a cohort of KTx who were candidates for IST reduction.

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Reduction in Maintenance Immunosuppression in Kidney Transplant Recipients With Stable Donor-Derived Cell-Free DNA Measurements: A Case Series

Cited by 5 publications

References 17 publications

Multi‐centre analytical performance verification of an IVD assay to quantify donor‐derived cell‐free DNA in solid organ transplant recipients

Multi‐centre analytical performance verification of an IVD assay to quantify donor‐derived cell‐free DNA in solid organ transplant recipients

Assessment of Donor Derived Cell Free DNA (dd-cfDNA) at Surveillance and at Clinical Suspicion of Acute Rejection in Renal Transplantation

Use of Donor-derived Cell-free DNA to Inform Tapering of Immunosuppression Therapy in Kidney Transplant Recipients: An Observational Study

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