Unrecognized sequence homologies may confound genome-wide association studies

Genome-wide association studies (GWAS) have become a preferred method to identify new genetic susceptibility loci. This technique aims to understanding the molecular etiology of common diseases, but in many cases, it has led to the identification of loci with no obvious biological relevance. Herein, we show that previously unrecognized sequence homologies have caused single-nucleotide polymorphism (SNP) microarrays to incorrectly associate a phenotype to a given locus when in fact the linkage is to another distant locus. Using genetic differences between male and female subjects as a model to study the effect of one specific genomic region on the whole SNP microarray, we provide strong evidence that the use of standard methods for GWAS can be misleading. We suggest a new systematic quality control step in the biological interpretation of previous and future GWAS

The Ets-1 transcription factor controls the development and function of natural regulatory T cells

Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1−/−) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1−/− mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1−/− T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1−/− T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1−/− T reg cells showed decreased in vitro suppression activity and did not protect Rag2−/− hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression

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

Pathogénie de la glomérulonéphrite expérimentale par anticorps anti membrane basale glomérulaire chez la souris (rôle des cellules INKT, de la vitronectine et du fond génétique)

PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Influence de la transplantation rénale sur la rigidité aortique au cours de la première année post greffe (étude d'une cohorte de 50 patients)

PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Red urine, updated for the nephrologist: a case report

International audienceBackgroundSickle cell trait is not completely benign, and some renal complications can occur. The baseline rate of admission for gross hematuria in normal males carrying the sickle cell trait is 2%.Case presentationA 35-year-old non-smoking African man experienced a 2-week history of painless, profuse and persistent gross hematuria. Laboratory tests showed normal renal function, hematuria and mild proteinuria. Abdominal ultrasonography and computed tomography angiography revealed no renal abnormalities; the bladder appeared pristine under cystoscopy. The diagnosis of sickle cell trait associated with gross hematuria was made using hemoglobin electrophoresis; renal biopsy and its complications were avoided. Urine was clear after 2 weeks of oral hydration and gamma epsilon-aminocaproic acid.ConclusionHemoglobin electrophoresis should be performed in cases of gross hematuria. Coupled with other non-invasive evaluation, this could avoid renal biopsy and its associated complications

Autoantibodies specific for the phospholipase A2 receptor in recurrent and De Novo membranous nephropathy.

International audienceRecent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A(2) receptor (PLA(2) R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti-PLA(2) R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA(2) R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA(2) R1 cDNA, and the presence of PLA(2) R1 antigen in immune deposits. We showed that PLA(2) R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA(2) R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA(2) R1-related idiopathic MN and anti-PLA(2) R1 antibodies at the time of transplantation will not develop recurrence. Because PLA(2) R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies

Development and validation of an alloscore in kidney transplantation

International audienc

Varia

La présente livraison du Courrier du Centre International Blaise Pascal reprend la formule du numéro 16, en proposant aux amis de Pascal les actes de la journée de travail sur Les Provinciales à Clermont par le CIBP, avec l’aide de son Université de tutelle. Le compte rendu en a été donné dans notre précédent numéro par Catherine Favereau, qui prépare actuellement une thèse de doctorat de stylistique pascalienne. Je n’ajouterai donc rien sur la substance de cette journée, qui a laissé un bon souvenir de travail efficace. Deux regrets ont tempéré la satisfaction des participants, l’absence d’un homme, notre ami Gérard Ferreyrolles qui n’avait pu se dégager de ses lourdes obligations professionnelles, et celle d’un livre, puisque le tome 5 des Œuvres complètes de Pascal éditées par Jean Mesnard, qui devait justement contenir les Provinciales, n’a pas pu paraître à temps pour transformer la journée de travail en célébration pascalienne. Ce sera pour une autre fois. Heureusement, à défaut de l’édition, nous avions l’éditeur. Comme directeur du CIBP, je souhaite souligner l’efficacité de la formule des journées de travail telles que nous les avons réalisées sur les Pensées, les trois ordres, Antoine Arnauld et Les Provinciales. Brèves mais intenses, elles permettent de faire le point au cours d’une réflexion commune dense, mettant en contact des chercheurs confirmés avec des étudiants à vocation pascalienne ou simplement attirés par les nécessités du programme universitaire. Le résultat en est toujours solide : on s’en assurera en lisant le volume édité par notre ami Jean-Claude Pariente sur Antoine Arnauld à la librairie philosophique Vrin, qui concrétise l’un des objectifs majeurs du CIBP, l’extension de ses relations au monde des spécialistes de la philosophie. La journée sur les trois ordres sera sans doute publiée prochainement par les soins de Martine Pécharman-Petit dans une revue philosophique. Enfin, la présente livraison permettra à nos amis de trouver le dernier état des travaux sur les Provinciales