Race-free estimated glomerular filtration rate equation in kidney transplant recipients:development and validation study

OBJECTIVE: To compare the performance of a newly developed race-free kidney recipient specific glomerular filtration rate (GFR) equation with the three current main equations for measuring GFR in kidney transplant recipients.DESIGN: Development and validation study SETTING: 17 cohorts in Europe, the United States, and Australia (14 transplant centres, three clinical trials).PARTICIPANTS: 15 489 adults (3622 in development cohort (Necker, Saint Louis, and Toulouse hospitals, France), 11 867 in multiple external validation cohorts) who received kidney transplants between 1 January 2000 and 1 January 2021.MAIN OUTCOME MEASURE: The main outcome measure was GFR, measured according to local practice. Performance of the GFR equations was assessed using P 30 (proportion of estimated GFR (eGFR) within 30% of measured GFR (mGFR)) and correct classification (agreement between eGFR and mGFR according to GFR stages). The race-free equation, based on creatinine level, age, and sex, was developed using additive and multiplicative linear regressions, and its performance was compared with the three current main GFR equations: Modification of Diet in Renal Disease (MDRD) equation, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation, and race-free CKD-EPI 2021 equation. RESULTS: The study included 15 489 participants, with 50 464 mGFR and eGFR values. The mean GFR was 53.18 mL/min/1.73m 2 (SD 17.23) in the development cohort and 55.90 mL/min/1.73m 2 (19.69) in the external validation cohorts. Among the current GFR equations, the race-free CKD-EPI 2021 equation showed the lowest performance compared with the MDRD and CKD-EPI 2009 equations. When race was included in the kidney recipient specific GFR equation, performance did not increase. The race-free kidney recipient specific GFR equation showed significantly improved performance compared with the race-free CKD-EPI 2021 equation and performed well in the external validation cohorts (P 30 ranging from 73.0% to 91.3%). The race-free kidney recipient specific GFR equation performed well in several subpopulations of kidney transplant recipients stratified by race (P 30 73.0-91.3%), sex (72.7-91.4%), age (70.3-92.0%), body mass index (64.5-100%), donor type (58.5-92.9%), donor age (68.3-94.3%), treatment (78.5-85.2%), creatinine level (72.8-91.3%), GFR measurement method (73.0-91.3%), and timing of GFR measurement post-transplant (72.9-95.5%). An online application was developed that estimates GFR based on recipient's creatinine level, age, and sex (https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/). CONCLUSION: A new race-free kidney recipient specific GFR equation was developed and validated using multiple, large, international cohorts of kidney transplant recipients. The equation showed high accuracy and outperformed the race-free CKD-EPI 2021 equation that was developed in individuals with native kidneys.TRIAL REGISTRATION: ClinicalTrials.gov NCT05229939.</p

SLK-dependent activation of ERMs controls LGN-NuMA localization and spindle orientation

International audienceMitotic spindle orientation relies on a complex dialog between the spindle microtubules and the cell cortex, in which F-actin has been recently implicated. Here, we report that the membrane-actin linkers ezrin/radixin/moesin (ERMs) are strongly and directly activated by the Ste20-like kinase at mitotic entry in mammalian cells. Using microfabricated adhesive substrates to control the axis of cell division, we found that the activation of ERMs plays a key role in guiding the orientation of the mitotic spindle. Accordingly, impairing ERM activation in apical progenitors of the mouse embryonic neocortex severely disturbed spindle orientation in vivo. At the molecular level, ERM activation promotes the polarized association at the mitotic cortex of leucine-glycine-asparagine repeat protein (LGN) and nuclear mitotic apparatus (NuMA) protein, two essential factors for spindle orientation. We propose that activated ERMs, together with Gαi, are critical for the correct localization of LGN-NuMA force generator complexes and hence for proper spindle orientation

External validation of prognostic scores for Covid-19: a multicentre cohort study of patients hospitalized in Greater Paris University Hospitals

International audienceThe Coronavirus disease 2019 (Covid-19) has led to an unparalleled influx of patients. Prognostic scores could help optimizing healthcare delivery, but most of them have not been comprehensively validated. We aim to externally validate existing prognostic scores for Covid-19. Methods We used "Covid-19 EvidenceAlerts" (McMaster University) to retrieve high-quality prognostic scores predicting death or intensive care unit (ICU) transfer from routinely collected data. We studied their accuracy in a retrospective multicentre cohort of adult patients hospitalized for Covid-19 from January 2020 to April 2021 in the Greater Paris University Hospitals. Areas under the receiver operating characteristic curves (AUC) were computed for the prediction of the original outcome, 30-day in-hospital mortality and the composite of 30-day in-hospital mortality or ICU transfer. Results We included 14,343 consecutive patients, 2,583 (18%) died and 5,067 (35%) died or were transferred to the ICU. We examined 274 studies and found 32 scores meeting the inclusion criteria: 19 had a significantly lower AUC in our cohort than in previously published validation studies for the original outcome; 25 performed better to predict in-hospital mortality than the composite of in-hospital mortality or ICU transfer; 7 had an AUC >0.75 to predict in-hospital mortality; 2 had an AUC >0.70 to predict the composite outcome. Conclusion Seven prognostic scores were fairly accurate to predict death in hospitalized Covid-19 patients. The 4C Mortality Score and the ABCS stand out because they performed as well in our cohort and their initial validation cohort, during the first epidemic wave and subsequent waves, and in younger and older patients

Regulatory T Cell Stability and Migration Are Dependent on mTOR

International audienceCD4+ Foxp3+ regulatory T cells (Treg) are essential to maintain immune tolerance, as their loss leads to a fatal autoimmune syndrome in mice and humans. Conflicting findings have been reported concerning their metabolism. Some reports found that Treg have low mechanistic target of rapamycin (mTOR) activity and would be less dependent on this kinase compared with conventional T cells, whereas other reports suggest quite the opposite. In this study, we revisited this question by using mice that have a specific deletion of mTOR in Treg. These mice spontaneously develop a severe and systemic inflammation. We show that mTOR expression by Treg is critical for their differentiation into effector Treg and their migration into nonlymphoid tissues. We also reveal that mTOR-deficient Treg have reduced stability. This loss of Foxp3 expression is associated with partial Foxp3 DNA remethylation, which may be due to an increased activity of the glutaminolysis pathway. Thus, our work shows that mTOR is crucial for Treg differentiation, migration, and identity and that drugs targeting this metabolism pathway will impact on their biology

Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

International audienceCD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell-mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients

Continuous Positive Airway Pressure (CPAP) face-mask ventilation is an easy and cheap option to manage a massive influx of patients presenting acute respiratory failure during the SARS-CoV-2 outbreak: A retrospective cohort study.

IntroductionBecause of the COVID-19 pandemic, intensive care units (ICU) can be overwhelmed by the number of hypoxemic patients.Material and methodsThis single centre retrospective observational cohort study took place in a French hospital where the number of patients exceeded the ICU capacity despite an increase from 18 to 32 beds. Because of this, 59 (37%) of the 159 patients requiring ICU care were referred to other hospitals. From 27th March to 23rd April, consecutive patients who had respiratory failure or were unable to maintain an SpO2 > 90%, despite receiving 10-15 l/min of oxygen with a non-rebreather mask, were treated by continuous positive airway pressure (CPAP) unless the ICU physician judged that immediate intubation was indicated. We describe the characteristics, clinical course, and outcomes of these patients. The main outcome under study was CPAP discontinuation.ResultsCPAP was initiated in 49 patients and performed out of ICU in 41 (84%). Median age was 65 years (IQR = 54-71) and 36 (73%) were men. Median respiratory rate before CPAP was 36 (30-40) and median SpO2 was 92% (90-95) under 10 to 15 L/min oxygen flow. Median duration of CPAP was 3 days (IQR = 1-5). Reasons for discontinuation of CPAP were: intubation in 25 (51%), improvement in 16 (33%), poor tolerance in 6 (12%) and death in 2 (4%) patients. A decision not to intubate had been taken for 8 patients, including the 2 who died while on CPAP. Two patients underwent less than one hour CPAP for poor tolerance. In the end, 15 (38%) out of 39 evaluable patients recovered with only CPAP whereas 24 (62%) were intubated.ConclusionsCPAP is feasible in a non-ICU environment in the context of massive influx of patients. In our cohort up to 1/3 of the patients presenting with acute respiratory failure recovered without intubation

Prognostic Biomarkers in Kidney Transplantation: a Systematic Review and Critical Appraisal.

peer reviewed[en] BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology and reporting might contribute to this phenomenon. METHODS: A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between 1 January 2005 and 12 November 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney-allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators. RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood (n=821, 71.8%), intragraft (n=169, 14.8%), or urine (n=81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (IQR: 23.8-35.5) between 2005 and 2012, and 57.5 (IQR: 53.3-59.8) between 2013 and 2022 (p<0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR: 96-629) with a median follow-up posttransplant of 4.8 years (IQR: 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies. CONCLUSIONS: and Relevance Biomarker studies in kidney transplantation lack validation, rigorous design, methods and interpretation, and transparency. Higher standards in biomarker research may improve the clinical utility and clinical use

Kidney Transplantation in Patients With AA Amyloidosis: Outcomes in a French Multicenter Cohort

International audienceRationale & ObjectiveOutcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, data are inconclusive and mostly based on studies from the early 2000s and earlier.Study DesignRetrospective multicenter cohort study.Setting & ParticipantsWe searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018.ExposuresAge, cause of amyloidosis, use of biotherapies, CRP levels.OutcomesOutcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events.Analytical ApproachThe Kaplan-Meier estimator for mortality and the cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively.ResultsEighty-six patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (interquartile range 39.7-61.1). The main cause of amyloidosis was Familial Mediterranean Fever (37 cases, 43%). Sixteen (18.6%) patients received a biotherapy after transplantation. Patient survival was 94.0% (95% confidence interval 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years post-transplantation. The cumulative incidence of allograft loss was 10.5% (4.0-17.0) at 1 year, and 13.0% (5.8-20.1) at 5 years post-transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). 55.8% of cases developed an infection requiring hospitalization and 27.9% acute allograft rejection. Multivariable analysis showed that CRP concentration at the time of transplantation was associated with patient survival (HR 1.01, 95% CI 1.00-1.02, p=0.01) and with allograft survival (HR 1.68, 95% CI 1.10-2.57, p 0.02).LimitationsThe study lacked a control group and the effect of biotherapies on transplantation outcomes could not be explored.ConclusionsThis relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease

External validation of prognostic scores for COVID-19: a multicenter cohort study of patients hospitalized in Greater Paris University Hospitals

International audiencePurposeThe Coronavirus disease 2019 (COVID-19) has led to an unparalleled influx of patients. Prognostic scores could help optimizing healthcare delivery, but most of them have not been comprehensively validated. We aim to externally validate existing prognostic scores for COVID-19.MethodsWe used “COVID-19 Evidence Alerts” (McMaster University) to retrieve high-quality prognostic scores predicting death or intensive care unit (ICU) transfer from routinely collected data. We studied their accuracy in a retrospective multicenter cohort of adult patients hospitalized for COVID-19 from January 2020 to April 2021 in the Greater Paris University Hospitals. Areas under the receiver operating characteristic curves (AUC) were computed for the prediction of the original outcome, 30-day in-hospital mortality and the composite of 30-day in-hospital mortality or ICU transfer.ResultsWe included 14,343 consecutive patients, 2583 (18%) died and 5067 (35%) died or were transferred to the ICU. We examined 274 studies and found 32 scores meeting the inclusion criteria: 19 had a significantly lower AUC in our cohort than in previously published validation studies for the original outcome; 25 performed better to predict in-hospital mortality than the composite of in-hospital mortality or ICU transfer; 7 had an AUC > 0.75 to predict in-hospital mortality; 2 had an AUC > 0.70 to predict the composite outcome.ConclusionSeven prognostic scores were fairly accurate to predict death in hospitalized COVID-19 patients. The 4C Mortality Score and the ABCS stand out because they performed as well in our cohort and their initial validation cohort, during the first epidemic wave and subsequent waves, and in younger and older patients