Donor-derived Cell-free DNA Research Articles

P.400: Assessing the efficacy of donor-derived cell-free DNA measurement in liver transplant recipients for rejection diagnosis and therapeutic response evaluation: A case report.

P.400: Assessing the efficacy of donor-derived cell-free DNA measurement in liver transplant recipients for rejection diagnosis and therapeutic response evaluation: A case report.

321.2: Clinical utility of donor-derived cell-free DNA during the period of recovery of renal function after kidney transplantation.

321.2: Clinical utility of donor-derived cell-free DNA during the period of recovery of renal function after kidney transplantation.

362.1: Increases in donor-derived cell-free DNA prior to biopsy proven rejection in kidney transplant.

362.1: Increases in donor-derived cell-free DNA prior to biopsy proven rejection in kidney transplant.

V-310.1: New prospective multicenter pOKRA study: Diagnosing allograft rejection and linking donor-derived cell-free DNA to interstitial fibrosis and cortical atrophy severity in pediatric kidney transplant rejection.

V-310.1: New prospective multicenter pOKRA study: Diagnosing allograft rejection and linking donor-derived cell-free DNA to interstitial fibrosis and cortical atrophy severity in pediatric kidney transplant rejection.

410.5: Donor-derived cell-free DNA identifies subclinical antibody-mediated rejection in de novo donor-specific antibody-positive kidney transplant recipients.

410.5: Donor-derived cell-free DNA identifies subclinical antibody-mediated rejection in de novo donor-specific antibody-positive kidney transplant recipients.

V-212.2: Enhancing pediatric kidney transplant rejection detection: Integrating donor-derived cell-free DNA fraction and quantity.

V-212.2: Enhancing pediatric kidney transplant rejection detection: Integrating donor-derived cell-free DNA fraction and quantity.

Noninvasive rejection surveillance after solid organ transplantations: analysis of the donor-derived cell-free DNA

A szolidszerv-transzplantátum kilökődése a modern immunszuppresszív kezelés mellett is a graftdiszfunkció, a hospitalizáció és a halálozás egyik fő etiológiai tényezője. A rejekció diagnosztikájában ’gold standard’ invazív biopszia azonban a hospitalizáció mellett számos szövődménnyel járhat, interpretálását nagy interobszerver variabilitás jellemzi. A rejekció megítélésében a noninvazív módszerek ezért nagy klinikai jelentőséggel bírnak. A graftkárosodást jellemző donoreredetű sejtmentes DNS (dd-cfDNA) a recipiens szérumából mutatható ki, szintje már a biopszia által igazolt kilökődést megelőzően emelkedést mutat, és magas negatív prediktív értékkel bír. Munkánk során a dd-cfDNA-assay szolid szerv (vese, máj, szív, tüdő, hasnyálmirigy) transzplantációját követően betöltött szerepét vizsgáltuk az elérhető irodalom összefoglalásával, továbbá a szívtranszplantáltak körében a rutin klinikai gyakorlatba 2022. októberben bevezetett dd-cfDNA-alapú rejekció utánkövetése során nyert első hazai eredményeinket kívánjuk megosztani. Cardialis allograftrejekció utánkövetése során 46 szívtranszplantált beteg 264 dd-cfDNA-mintáját elemeztük. Az eredmény a keringő donoreredetű sejtmentes DNS és a plazma teljes (recipiens- és donoreredetű) sejtmentes DNS arányát mutatja: a ≥0,20% dd-cfDNA-érték károsodásra, míg a ≥0,35% dd-cfDNA-szint súlyos graftkárosodásra utal. A dd-cfDNA-minták 80%-a <0,20% értéket mutatott. Myocardium-károsodásra utaló dd-cfDNA-érték következtében összesen 20 szívizom-biopsziát végeztünk: kilökődés 6 esetben igazolódott. 16 hónap során 232, a reguláris surveillance-biopsziák 88%-a biztonságosan elhagyható volt a dd-cfDNA-értékek alapján. A korai graftkárosodás kimutatása által lehetőség nyílik az immunszuppresszív terápia korai és személyre szabott módosítására a súlyosabb fokú kilökődés és az irreverzibilis graftkárosodás megelőzése, illetve a gyógyszertoxicitás elkerülése érdekében. Orv Hetil. 2024; 165(33): 1275–1285.

Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices.

The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. ClinicalTrials.gov: NCT03719339.

Antibody-Mediated Rejection in Lung Transplantation: Diagnosis and Therapeutic Armamentarium in a 21st Century Perspective.

Humoral immunity is a major waypoint towards chronic allograft dysfunction in lung transplantation (LT) recipients. Though allo-immunization and antibody-mediated rejection (AMR) are well-known entities, some diagnostic gaps need to be addressed. Morphological analysis could be enhanced by digital pathology and artificial intelligence-based companion tools. Graft transcriptomics can help to identify graft failure phenotypes or endotypes. Donor-derived cell free DNA is being evaluated for graft-loss risk stratification and tailored surveillance. Preventative therapies should be tailored according to risk. The donor pool can be enlarged for candidates with HLA sensitization, with strategies combining plasma exchange, intravenous immunoglobulin and immune cell depletion, or with emerging or innovative therapies such as imlifidase or immunoadsorption. In cases of insufficient pre-transplant desensitization, the effects of antibodies on the allograft can be prevented by targeting the complement cascade, although evidence for this strategy in LT is limited. In LT recipients with a humoral response, strategies are combined, including depletion of immune cells (plasmapheresis or immunoadsorption), inhibition of immune pathways, or modulation of the inflammatory cascade, which can be achieved with photopheresis. Altogether, these innovative techniques offer promising perspectives for LT recipients and shape the 21st century's armamentarium against AMR.

Rejection Surveillance After Heart Transplantation: Is Paired Noninvasive Testing the New Gold Standard?

Rejection surveillance after heart transplantation has traditionally relied on numerous endomyocardial biopsies, most of which occur during the first posttransplant year. With the introduction of gene expression profiling and, more recently, donor-derived cell-free DNA, a great proportion of surveillance is being performed noninvasively with both tests. Although patients have welcomed the use of paired testing because of the decreased risk and inconvenience, interpretation of both tests can sometimes be challenging, particularly when the test results are discordant. Growing evidence from both single-center experiences and large national databases has given insights that have allowed the field to operationalize dual testing and provide physicians with algorithms to approach paired testing. The increased use of noninvasive testing has also begun to challenge the role of biopsy as the gold standard for graft monitoring, not only for rejection but over the life of the heart transplant. In a growing number of circumstances, cell-free DNA not only may be a better means of assessing rejection but could also redefine how clinicians approach the diagnosis and even treatment of graft injury. As the heart transplant community garners more experience and generates more data, the current paradigms of heart transplant surveillance will continue to be challenged.

Baseline Lung Allograft Dysfunction After Bilateral Lung Transplantation Is Associated With an Increased Risk of Death: Results From a Multicenter Cohort Study.

A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; P = 0.15). BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection

BackgroundAntibody-mediated rejection is a leading cause of kidney-transplant failure. The targeting of CD38 to inhibit graft injury caused by alloantibodies and natural killer (NK) cells may be a therapeutic option.MethodsIn this phase 2, double-blind, randomized, placebo-controlled trial, we assigned patients with antibody-mediated rejection that had occurred at least 180 days after transplantation to receive nine infusions of the CD38 monoclonal antibody felzartamab (at a dose of 16 mg per kilogram of body weight) or placebo for 6 months, followed by a 6-month observation period. The primary outcome was the safety and side-effect profile of felzartamab. Key secondary outcomes were renal-biopsy results at 24 and 52 weeks, donor-specific antibody levels, peripheral NK-cell counts, and donor-derived cell-free DNA levels.ResultsA total of 22 patients underwent randomization (11 to receive felzartamab and 11 to receive placebo). The median time from transplantation until trial inclusion was 9 years. Mild or moderate infusion reactions occurred in 8 patients in the felzartamab group. Serious adverse events occurred in 1 patient in the felzartamab group and in 4 patients in the placebo group; graft loss occurred in 1 patient in the placebo group. At week 24, resolution of morphologic antibody-mediated rejection was more frequent with felzartamab (in 9 of 11 patients [82%]) than with placebo (in 2 of 10 patients [20%]), for a difference of 62 percentage points (95% confidence interval [CI], 19 to 100) and a risk ratio of 0.23 (95% confidence interval [CI], 0.06 to 0.83). The median microvascular inflammation score was lower in the felzartamab group than in the placebo group (0 vs. 2.5), for a mean difference of −1.95 (95% CI, −2.97 to −0.92). Also lower was a molecular score reflecting the probability of antibody-mediated rejection (0.17 vs. 0.77) and the level of donor-derived cell-free DNA (0.31% vs. 0.82%). At week 52, the recurrence of antibody-mediated rejection was reported in 3 of 9 patients who had a response to felzartamab, with an increase in molecular activity and biomarker levels toward baseline levels.ConclusionsFelzartamab had acceptable safety and side-effect profiles in patients with antibody-mediated rejection. (Funded by MorphoSys and Human Immunology Biosciences; ClinicalTrials.gov number, NCT05021484; and EUDRACT number, 2021-000545-40.)

Immune monitoring in pediatric kidney transplant.

Long-term outcomes in pediatric kidney transplantation remain suboptimal, largely related to chronic rejection. Creatinine is a late marker of renal injury, and more sensitive, early markers of allograft injury are an active area of current research. This is an educational review summarizing existing strategies for monitoring for rejection in kidney transplant recipients. We summarize supporting currently available clinical tests, including surveillance biopsy, donor specific antibodies, and donor-derived cell free DNA, as well as the potential limitations of these studies. In addition, we review the current avenues of active research, including transcriptomics, proteomics, metabolomics, and torque tenovirus levels. Advancing the use of noninvasive immune monitoring will depend on well-designed multicenter trials that include patients with stable graft function, include biopsy results on all patients, and can demonstrate both association with a patient-relevant clinical endpoint such as graft survival or change in glomerular filtration rate and a potential timepoint for intervention.

Donor-derived Cell-free DNA and Acute Kidney Rejection: A Golden Opportunity or a False Hope?

Donor-derived Cell-free DNA and Acute Kidney Rejection: A Golden Opportunity or a False Hope?

(398) - Donor-Derived Cell-Free DNA is Elevated in Donation After Circulatory Death

(398) - Donor-Derived Cell-Free DNA is Elevated in Donation After Circulatory Death

(1342) - Donor-Derived Cell-Free DNA in Pediatric Heart Transplant Patients

(1342) - Donor-Derived Cell-Free DNA in Pediatric Heart Transplant Patients

(1118) - Impact of Induction Therapy on Gene Expression Profiling and Donor Derived Cell Free DNA

(1118) - Impact of Induction Therapy on Gene Expression Profiling and Donor Derived Cell Free DNA

(784) - Donor Derived Cell Free DNA is a Reliable Marker in High Risk Heart Transplant Patients

(784) - Donor Derived Cell Free DNA is a Reliable Marker in High Risk Heart Transplant Patients

(871) - Donor Derived Cell Free DNA, Gene Expression Profiles and Acute Rejection in Donation After Circulatory Death (DCD) Heart Transplant Recipients

(871) - Donor Derived Cell Free DNA, Gene Expression Profiles and Acute Rejection in Donation After Circulatory Death (DCD) Heart Transplant Recipients

(794) - Clinical Utility of Combination Testing of Gene-Expression Profiling and Donor-Derived Cell-Free DNA in Heart Transplantation

(794) - Clinical Utility of Combination Testing of Gene-Expression Profiling and Donor-Derived Cell-Free DNA in Heart Transplantation