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A Randomized Phase 2 Trial of Felzartamab in Antibody-Mediated Rejection
Antibody-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.
In 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.
A 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.
Felzartamab 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.).
Journal Article
Objections! : the ultimate guide to mastering the art and science of getting past no
\"Following in the footsteps of his blockbuster bestsellers Fanatical Prospecting and Sales EQ, Jeb Blount's Objections is a comprehensive and contemporary guide that engages your heart and mind. In his signature right-to-the-point style, Jeb pulls no punches and slaps you in the face with the cold, hard truth about what's really holding you back from closing sales and reaching your income goals. Then he pulls you in with examples, stories, and lessons that teach powerful human-influence frameworks for getting past NO - even with the most challenging objections\"-- Provided by publisher.
Book
Gene-Expression Profiling for Rejection Surveillance after Cardiac Transplantation
Patients were assigned to monitoring for rejection after cardiac transplantation either according to the standard practice of endomyocardial biopsies or with gene-expression profiling. At 19 months, the rates of rejection with hemodynamic compromise, graft dysfunction, death, or retransplantation were similar in the two groups, although the power of the trial was limited.
Patients were assigned to monitoring for rejection after cardiac transplantation either according to the standard practice of endomyocardial biopsies or with gene-expression profiling. At 19 months, the rates of rejection were similar in the two groups.
Advances in immunosuppression after cardiac transplantation have increased the rates of 1-year survival among recipients to nearly 90%. However, acute cellular rejection is still observed during the first year after transplantation (at a rate of approximately 30 to 40%) and occurs at a lower rate thereafter.
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Rejection episodes are associated with an increased risk of allograft vasculopathy and loss.
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Endomyocardial biopsy has remained the primary method of monitoring for rejection, despite the discomfort and the rare but potentially serious complications of the procedure.
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Quantitative assessment of mononuclear-cell gene expression in peripheral-blood specimens has been explored as a . . .
Journal Article
Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study
AbstractObjectiveTo develop and validate an integrative system to predict long term kidney allograft failure.DesignInternational cohort study.SettingThree cohorts including kidney transplant recipients from 10 academic medical centres from Europe and the United States.ParticipantsDerivation cohort: 4000 consecutive kidney recipients prospectively recruited in four French centres between 2005 and 2014. Validation cohorts: 2129 kidney recipients from three centres in Europe and 1428 from three centres in North America, recruited between 2002 and 2014. Additional validation in three randomised controlled trials (NCT01079143, EudraCT 2007-003213-13, and NCT01873157).Main outcome measureAllograft failure (return to dialysis or pre-emptive retransplantation). 32 candidate prognostic factors for kidney allograft survival were assessed.ResultsAmong the 7557 kidney transplant recipients included, 1067 (14.1%) allografts failed after a median post-transplant follow-up time of 7.12 (interquartile range 3.51-8.77) years. In the derivation cohort, eight functional, histological, and immunological prognostic factors were independently associated with allograft failure and were then combined into a risk prediction score (iBox). This score showed accurate calibration and discrimination (C index 0.81, 95% confidence interval 0.79 to 0.83). The performance of the iBox was also confirmed in the validation cohorts from Europe (C index 0.81, 0.78 to 0.84) and the US (0.80, 0.76 to 0.84). The iBox system showed accuracy when assessed at different times of evaluation post-transplant, was validated in different clinical scenarios including type of immunosuppressive regimen used and response to rejection therapy, and outperformed previous risk prediction scores as well as a risk score based solely on functional parameters including estimated glomerular filtration rate and proteinuria. Finally, the accuracy of the iBox risk score in predicting long term allograft loss was confirmed in the three randomised controlled trials.ConclusionAn integrative, accurate, and readily implementable risk prediction score for kidney allograft failure has been developed, which shows generalisability across centres worldwide and common clinical scenarios. The iBox risk prediction score may help to guide monitoring of patients and further improve the design and development of a valid and early surrogate endpoint for clinical trials.Trial registrationClinicaltrials.gov NCT03474003.
Journal Article
Biopsy proteome-based classification of T cell-mediated kidney allograft rejection
Background
T cell-mediated rejection (TCMR) remains a challenge in kidney transplantation. Based on a histopathological biopsy examination, patients can be classified into groups such as no rejection (NR), borderline rejection (BR; Banff category 3), and acute rejection (AR; Banff category 4). Yet, this classification is not sufficient, since for the borderline cases a number of patients may require a clinical intervention. Thus, a robust classification by biopsy proteome profiling may provide a solution.
Methods
In this work, kidney tissue from patients classified into NR, BR, and AR were subjected to MS-based proteomic profiling. Subsequently, a panel of four proteins (GNB4, PDK1, AGXT, CD73) was selected for validation by immunohistochemistry (IHC). This retrospective study was approved by the Bioethics Committee of the Medical University of Gdańsk, no. NKBBN/201/2021.
Results
Proteomic analysis identified 2547 proteins whose abundance profiles demonstrated strong concordance between the BR and AR groups. In a quantitative comparison between the BR and AR groups, GNB4 and AGXT emerged as significantly differentiating. Moreover, AGXT was indicated as a potential biomarker following ROC analysis. PDK1 and CD73 were found to best classify the samples in a binary analysis. IHC confirmed only upregulation of GNB4 in immune cells and PDK1 in macrophages, with no significant changes in the tubular epithelium.
Conclusions
Thus, GNB4 and PDK1 in immune cells and macrophages have been identified as a potential target for further extensive studies. If their relevance were to be confirmed in a larger patient cohort, their IHC analysis could serve as an extension of established histopathological classification in the context of kidney transplant rejection.
Journal Article
Cell-free DNA for the detection of kidney allograft rejection
Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (
P
< 0.0001), T cell-mediated rejection (
P
< 0.0001) and mixed rejection (
P
< 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902–2.739;
P
< 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741–0.811) to 0.821 (95% CI 0.784–0.852);
P
= 0.0011) and calibration. These results were confirmed in the external validation cohorts (
n
= 1,748) including a cohort of African American patients (
n
= 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration:
NCT05995379
.
A prospective observational study including 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States shows that cell-free DNA can be used to detect kidney allograft rejection.
Journal Article