Monitoring of Serological, Cellular and Genomic Biomarkers in Transplantation, Computational Prediction Models and Role of Cell-Free DNA in Transplant Outcome (original) (raw)
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Nephrology Dialysis Transplantation, 2019
Background After transplantation, cell-free deoxyribonucleic acid (DNA) derived from the donor organ (ddcfDNA) can be detected in the recipient’s circulation. We aimed to investigate the role of plasma ddcfDNA as biomarker for acute kidney rejection. Methods From 107 kidney transplant recipients, plasma samples were collected longitudinally after transplantation (Day 1 to 3 months) within a multicentre set-up. Cell-free DNA from the donor was quantified in plasma as a fraction of the total cell-free DNA by next generation sequencing using a targeted, multiplex polymerase chain reaction-based method for the analysis of single nucleotide polymorphisms. Results Increases of the ddcfDNA% above a threshold value of 0.88% were significantly associated with the occurrence of episodes of acute rejection (P = 0.017), acute tubular necrosis (P = 0.011) and acute pyelonephritis (P = 0.032). A receiver operating characteristic curve analysis revealed an equal area under the curve of the ddcfDNA...
Journal of the American Society of Nephrology, 2021
Early detection of allograft rejection is critical to the successful management of transplant recipients. Tissue biopsy has been the "gold standard" for diagnosis of active rejection (AR), but is invasive and has poor reproducibility. 1 Conventional noninvasive biomarkers, such as changes in serum creatinine, are available for detecting AR, but are limited due to low sensitivity and specificity. 2 Thus, there is a need for new noninvasive markers that have high accuracy for detecting AR. Donor-derived cell-free DNA fraction (dd-cfDNA[%]) is a promising noninvasive biomarker for detecting allograft rejection. However, dd-cfDNA(%) can be artificially depressed by high levels of circulating cfDNA, which can occur in patients who are obese, have had recent surgery, have medical complications, or received certain medications. 3 This can potentially lead to false negative results. Recently, two studies provided preliminary evidence indicating that the absolute quantity of dd-cfDNA may show better performance for detecting AR than dd-cfDNA(%). 4,5 In this study we present our results from an assay that utilizes a new two-threshold algorithm that combines both dd-cfDNA(%) and absolute quantity of dd-cfDNA (copies/ml), with the goal of increasing test sensitivity, particularly through improved detection in patients where cfDNA levels are high.
Journal of Clinical Medicine
Standard noninvasive methods for detecting renal allograft rejection and injury have poor sensitivity and specificity. Plasma donor-derived cell-free DNA (dd-cfDNA) has been reported to accurately detect allograft rejection and injury in transplant recipients and shown to discriminate rejection from stable organ function in kidney transplant recipients. This study used a novel single nucleotide polymorphism (SNP)-based massively multiplexed PCR (mmPCR) methodology to measure dd-cfDNA in various types of renal transplant recipients for the detection of allograft rejection/injury without prior knowledge of donor genotypes. A total of 300 plasma samples (217 biopsy-matched: 38 with active rejection (AR), 72 borderline rejection (BL), 82 with stable allografts (STA), and 25 with other injury (OI)) were collected from 193 unique renal transplant patients; dd- cfDNA was processed by mmPCR targeting 13,392 SNPs. Median dd-cfDNA was significantly higher in samples with biopsy-proven AR (2.3...
Biomarkers in renal transplantation: An updated review
World Journal of Transplantation
Genomics, proteomics and molecular biology lead to tremendous advances in all fields of medical sciences. Among these the finding of biomarkers as non invasive indicators of biologic processes represents a useful tool in the field of transplantation. In addition to define the principal characteristics of the biomarkers, this review will examine the biomarker usefulness in the different clinical phases following renal transplantation. Biomarkers of ischemia-reperfusion injury and of delayed graft function are extremely important for an early diagnosis of these complications and for optimizing the treatment. Biomarkers predicting or diagnosing acute rejection either cell-mediated or antibody-mediated allow a risk stratification of the recipient, a prompt diagnosis in an early phase when the histology is still unremarkable. The kidney solid organ response test detects renal transplant recipients at high risk for acute rejection with a very high sensitivity and is also able to make diagnosis of subclinical acute rejection. Other biomarkers are able to detect chronic allograft dysfunction in an early phase and to differentiate the true chronic rejection from other forms of chronic allograft nephropathies no immune related. Finally biomarkers recently discovered identify patients tolerant or almost tolerant. This fact allows to safely reduce or withdrawn the immunosuppressive therapy.
Journal of Personalized Medicine
Renal transplantation is the definitive therapy for patients suffering from end-stage renal disease. Though there have been significant advances in immunosuppression in these patients, there is still up to 30% acute and subclinical rejection. Current standards employ lab markers of renal function and biopsy results for accurate diagnosis. However, donor derived cell-free DNA has been identified as a measurable lab test that may be able to adequately diagnose rejection at early stages, precluding the need for invasive procedures like biopsy. We obtained published data directly from companies that offer ddcfDNA assay tests and additionally conducted a literature review using databases like PUBMED and NIH U.S. National Library of Medicine. We comprehensively compare the most used ddcfDNA assays, delineate their respective limitations, and further explore future directions in the utility of ddcfDNA in renal transplant patients.
Journal of Clinical Medicine, 2021
Kidney transplantation (KTx) is the best treatment method for end-stage kidney disease. KTx improves the patient’s quality of life and prolongs their survival time; however, not all patients benefit fully from the transplantation procedure. For some patients, a problem is the premature loss of graft function due to immunological or non-immunological factors. Circulating cell-free DNA (cfDNA) is degraded deoxyribonucleic acid fragments that are released into the blood and other body fluids. Donor-derived cell-free DNA (dd-cfDNA) is cfDNA that is exogenous to the patient and comes from a transplanted organ. As opposed to an invasive biopsy, dd-cfDNA can be detected by a non-invasive analysis of a sample. The increase in dd-cfDNA concentration occurs even before the creatinine level starts rising, which may enable early diagnosis of transplant injury and adequate treatment to avoid premature graft loss. In this paper, we summarise the latest promising results related to cfDNA in transp...
Molecular Markers of Kidney Transplantation Outcome: Current Omics Tools and Future Developments
International Journal of Molecular Sciences
Purpose of review: The emerging field of molecular predictive medicine is aiming to change the traditional medical approach in renal transplantation. Many studies have explored potential biomarker molecules with predictive properties in renal transplantation, issued from omics research. Herein, we review the biomarker molecules of four technologies (i.e., Genomics, Transcriptomics, Proteomics, and Metabolomics) associated with favorable kidney transplant outcomes. Recent findings: Several panels of molecules have been associated with the outcome that the majority of markers are related to inflammation and immune response; although. other molecular ontologies are also represented, such as proteasome, growth, regeneration, and drug metabolism. Throughout this review, we highlight the lack of properly validated statistical demonstration. Indeed, the most preeminent molecular panels either remain at the limited size study stage or are not confirmed during large-scale studies. At the cor...