Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Rôle des récepteurs au S1P et de leur combinatoire dans la migration des lymphocytes T : chez l'homme et chez la souris

T cell,migration,sphingosine-1-phosphate,S1P receptorT cell exit from lymphoid organs is mediated by sphingosine-1-phosphate (S1P). S1P is produced at high concentration in blood and lymph and attracts T cells to promote their exit from primary or secondary lymphoid organs (PLO and SLO) wherein S1P concentration is low. S1P can bind to five G protein coupled receptors (S1PR1-5). Even though some of those receptors are already targeted in medical treatments such as multiple sclerosis, knowledge about S1P implication in human T cell trafficking as well as S1PR combination role in this context remain parcellar. Thus, we want to decipher the role of S1PR and their combination in human T cell migration. We previously highlighted the antagonism between S1PR1 and S1PR2 in the control of T cell egress from human SLO. Furthermore, contrary to S1PR1 requirement for naïve T cell migration, Natural Killer (NK) cells were shown to preferentially use S1PR5 to exit bone marrow and SLO. Therefore, this thesis project focuses on two axes : on one hand the functional antagonism between S1PR1 and S1PR2, on the other hand the differences between S1PR1 and S1PR5. The balance between S1PR1 and S1PR2 expression was shown to impact Jurkat migratory response, with S1PR1 decreasing spontaneous migration and increasing migration towards S1P, and S1PR2 inducing the opposite effect at low concentrations of S1P. We also highlighted the inability of S1P to induced S1PR5 internalization, contrary to S1PR1 and S1PR2. Finally, these results underline functional differences between S1PR that lead to different cellular responses to the same ligandLe sphingosine-1-phosphate (S1P) régule la sortie des lymphocytes T des organes lymphoïdes secondaires (OLS). Sa forte concentration dans le sang et la lymphe permet d’attirer les lymphocytes T hors des OLS, où la concentration en S1P est faible. Le S1P peut se lier à cinq récepteurs membranaires (S1PR1-5) exprimés en combinatoires variables par les différentes sous-populations de lymphocytes T. On connaît actuellement assez mal le rôle du S1P dans la recirculation lymphocytaire chez l’homme, ainsi que le rôle des combinatoires des S1PR dans ce contexte. Nous souhaitons donc comprendre comment les récepteurs au S1P et leur combinatoire régulent la migration des lymphocytes T. Nous avons précédemment souligné l’existence d’un antagonisme entre S1PR1 et S1PR2 dans le contrôle de la sortie des lymphocytes T des OLS. Il a également été montré que, si S1PR1 était essentiel à la migration des lymphocytes T naïfs, les lymphocytes Natural Killer utilisaient préférentiellement S1PR5 pour sortie de la moelle osseuse et des OLS. De ce fait, ce projet de thèse se concentre sur deux axes : d’une part l’antagonisme fonctionnel entre S1PR1 et S1PR2, d’autre part la différence entre S1PR1 et S1PR5. Nous avons montré que la balance entre l’expression de S1PR1 et S1PR2 influençait fortement la réponse migratoire des Jurkat, S1PR1 réduisant la migration spontanée et augmentant la migration au S1P, et S1PR2 induisant l’effet inverse à faible dose de S1P. Nous avons également mis en évidence l’absence d’internalisation de S1PR5 par le S1P, à l’inverse de S1PR1 et S1PR2. Finalement, ces résultats soulignent des différences fonctionnelles entre les S1PR, qui permettent d’obtenir des réponses différentes à un même ligan

Role of S1P receptors and their combination in T cell migration : in human and mouse

Le sphingosine-1-phosphate (S1P) régule la sortie des lymphocytes T des organes lymphoïdes secondaires (OLS). Sa forte concentration dans le sang et la lymphe permet d’attirer les lymphocytes T hors des OLS, où la concentration en S1P est faible. Le S1P peut se lier à cinq récepteurs membranaires (S1PR1-5) exprimés en combinatoires variables par les différentes sous-populations de lymphocytes T. On connaît actuellement assez mal le rôle du S1P dans la recirculation lymphocytaire chez l’homme, ainsi que le rôle des combinatoires des S1PR dans ce contexte. Nous souhaitons donc comprendre comment les récepteurs au S1P et leur combinatoire régulent la migration des lymphocytes T. Nous avons précédemment souligné l’existence d’un antagonisme entre S1PR1 et S1PR2 dans le contrôle de la sortie des lymphocytes T des OLS. Il a également été montré que, si S1PR1 était essentiel à la migration des lymphocytes T naïfs, les lymphocytes Natural Killer utilisaient préférentiellement S1PR5 pour sortie de la moelle osseuse et des OLS. De ce fait, ce projet de thèse se concentre sur deux axes : d’une part l’antagonisme fonctionnel entre S1PR1 et S1PR2, d’autre part la différence entre S1PR1 et S1PR5. Nous avons montré que la balance entre l’expression de S1PR1 et S1PR2 influençait fortement la réponse migratoire des Jurkat, S1PR1 réduisant la migration spontanée et augmentant la migration au S1P, et S1PR2 induisant l’effet inverse à faible dose de S1P. Nous avons également mis en évidence l’absence d’internalisation de S1PR5 par le S1P, à l’inverse de S1PR1 et S1PR2. Finalement, ces résultats soulignent des différences fonctionnelles entre les S1PR, qui permettent d’obtenir des réponses différentes à un même ligandT cell,migration,sphingosine-1-phosphate,S1P receptorT cell exit from lymphoid organs is mediated by sphingosine-1-phosphate (S1P). S1P is produced at high concentration in blood and lymph and attracts T cells to promote their exit from primary or secondary lymphoid organs (PLO and SLO) wherein S1P concentration is low. S1P can bind to five G protein coupled receptors (S1PR1-5). Even though some of those receptors are already targeted in medical treatments such as multiple sclerosis, knowledge about S1P implication in human T cell trafficking as well as S1PR combination role in this context remain parcellar. Thus, we want to decipher the role of S1PR and their combination in human T cell migration. We previously highlighted the antagonism between S1PR1 and S1PR2 in the control of T cell egress from human SLO. Furthermore, contrary to S1PR1 requirement for naïve T cell migration, Natural Killer (NK) cells were shown to preferentially use S1PR5 to exit bone marrow and SLO. Therefore, this thesis project focuses on two axes : on one hand the functional antagonism between S1PR1 and S1PR2, on the other hand the differences between S1PR1 and S1PR5. The balance between S1PR1 and S1PR2 expression was shown to impact Jurkat migratory response, with S1PR1 decreasing spontaneous migration and increasing migration towards S1P, and S1PR2 inducing the opposite effect at low concentrations of S1P. We also highlighted the inability of S1P to induced S1PR5 internalization, contrary to S1PR1 and S1PR2. Finally, these results underline functional differences between S1PR that lead to different cellular responses to the same ligan

Rôle des récepteurs au S1P et de leur combinatoire dans la migration des lymphocytes T : chez l'homme et chez la souris

T cell,migration,sphingosine-1-phosphate,S1P receptorT cell exit from lymphoid organs is mediated by sphingosine-1-phosphate (S1P). S1P is produced at high concentration in blood and lymph and attracts T cells to promote their exit from primary or secondary lymphoid organs (PLO and SLO) wherein S1P concentration is low. S1P can bind to five G protein coupled receptors (S1PR1-5). Even though some of those receptors are already targeted in medical treatments such as multiple sclerosis, knowledge about S1P implication in human T cell trafficking as well as S1PR combination role in this context remain parcellar. Thus, we want to decipher the role of S1PR and their combination in human T cell migration. We previously highlighted the antagonism between S1PR1 and S1PR2 in the control of T cell egress from human SLO. Furthermore, contrary to S1PR1 requirement for naïve T cell migration, Natural Killer (NK) cells were shown to preferentially use S1PR5 to exit bone marrow and SLO. Therefore, this thesis project focuses on two axes : on one hand the functional antagonism between S1PR1 and S1PR2, on the other hand the differences between S1PR1 and S1PR5. The balance between S1PR1 and S1PR2 expression was shown to impact Jurkat migratory response, with S1PR1 decreasing spontaneous migration and increasing migration towards S1P, and S1PR2 inducing the opposite effect at low concentrations of S1P. We also highlighted the inability of S1P to induced S1PR5 internalization, contrary to S1PR1 and S1PR2. Finally, these results underline functional differences between S1PR that lead to different cellular responses to the same ligandLe sphingosine-1-phosphate (S1P) régule la sortie des lymphocytes T des organes lymphoïdes secondaires (OLS). Sa forte concentration dans le sang et la lymphe permet d’attirer les lymphocytes T hors des OLS, où la concentration en S1P est faible. Le S1P peut se lier à cinq récepteurs membranaires (S1PR1-5) exprimés en combinatoires variables par les différentes sous-populations de lymphocytes T. On connaît actuellement assez mal le rôle du S1P dans la recirculation lymphocytaire chez l’homme, ainsi que le rôle des combinatoires des S1PR dans ce contexte. Nous souhaitons donc comprendre comment les récepteurs au S1P et leur combinatoire régulent la migration des lymphocytes T. Nous avons précédemment souligné l’existence d’un antagonisme entre S1PR1 et S1PR2 dans le contrôle de la sortie des lymphocytes T des OLS. Il a également été montré que, si S1PR1 était essentiel à la migration des lymphocytes T naïfs, les lymphocytes Natural Killer utilisaient préférentiellement S1PR5 pour sortie de la moelle osseuse et des OLS. De ce fait, ce projet de thèse se concentre sur deux axes : d’une part l’antagonisme fonctionnel entre S1PR1 et S1PR2, d’autre part la différence entre S1PR1 et S1PR5. Nous avons montré que la balance entre l’expression de S1PR1 et S1PR2 influençait fortement la réponse migratoire des Jurkat, S1PR1 réduisant la migration spontanée et augmentant la migration au S1P, et S1PR2 induisant l’effet inverse à faible dose de S1P. Nous avons également mis en évidence l’absence d’internalisation de S1PR5 par le S1P, à l’inverse de S1PR1 et S1PR2. Finalement, ces résultats soulignent des différences fonctionnelles entre les S1PR, qui permettent d’obtenir des réponses différentes à un même ligan

Rôle des récepteurs au S1P et de leur combinatoire dans la migration des lymphocytes T : chez l'homme et chez la souris

T cell,migration,sphingosine-1-phosphate,S1P receptorT cell exit from lymphoid organs is mediated by sphingosine-1-phosphate (S1P). S1P is produced at high concentration in blood and lymph and attracts T cells to promote their exit from primary or secondary lymphoid organs (PLO and SLO) wherein S1P concentration is low. S1P can bind to five G protein coupled receptors (S1PR1-5). Even though some of those receptors are already targeted in medical treatments such as multiple sclerosis, knowledge about S1P implication in human T cell trafficking as well as S1PR combination role in this context remain parcellar. Thus, we want to decipher the role of S1PR and their combination in human T cell migration. We previously highlighted the antagonism between S1PR1 and S1PR2 in the control of T cell egress from human SLO. Furthermore, contrary to S1PR1 requirement for naïve T cell migration, Natural Killer (NK) cells were shown to preferentially use S1PR5 to exit bone marrow and SLO. Therefore, this thesis project focuses on two axes : on one hand the functional antagonism between S1PR1 and S1PR2, on the other hand the differences between S1PR1 and S1PR5. The balance between S1PR1 and S1PR2 expression was shown to impact Jurkat migratory response, with S1PR1 decreasing spontaneous migration and increasing migration towards S1P, and S1PR2 inducing the opposite effect at low concentrations of S1P. We also highlighted the inability of S1P to induced S1PR5 internalization, contrary to S1PR1 and S1PR2. Finally, these results underline functional differences between S1PR that lead to different cellular responses to the same ligandLe sphingosine-1-phosphate (S1P) régule la sortie des lymphocytes T des organes lymphoïdes secondaires (OLS). Sa forte concentration dans le sang et la lymphe permet d’attirer les lymphocytes T hors des OLS, où la concentration en S1P est faible. Le S1P peut se lier à cinq récepteurs membranaires (S1PR1-5) exprimés en combinatoires variables par les différentes sous-populations de lymphocytes T. On connaît actuellement assez mal le rôle du S1P dans la recirculation lymphocytaire chez l’homme, ainsi que le rôle des combinatoires des S1PR dans ce contexte. Nous souhaitons donc comprendre comment les récepteurs au S1P et leur combinatoire régulent la migration des lymphocytes T. Nous avons précédemment souligné l’existence d’un antagonisme entre S1PR1 et S1PR2 dans le contrôle de la sortie des lymphocytes T des OLS. Il a également été montré que, si S1PR1 était essentiel à la migration des lymphocytes T naïfs, les lymphocytes Natural Killer utilisaient préférentiellement S1PR5 pour sortie de la moelle osseuse et des OLS. De ce fait, ce projet de thèse se concentre sur deux axes : d’une part l’antagonisme fonctionnel entre S1PR1 et S1PR2, d’autre part la différence entre S1PR1 et S1PR5. Nous avons montré que la balance entre l’expression de S1PR1 et S1PR2 influençait fortement la réponse migratoire des Jurkat, S1PR1 réduisant la migration spontanée et augmentant la migration au S1P, et S1PR2 induisant l’effet inverse à faible dose de S1P. Nous avons également mis en évidence l’absence d’internalisation de S1PR5 par le S1P, à l’inverse de S1PR1 et S1PR2. Finalement, ces résultats soulignent des différences fonctionnelles entre les S1PR, qui permettent d’obtenir des réponses différentes à un même ligan

Human Naive and Memory T Cells Display Opposite Migratory Responses to Sphingosine-1 Phosphate

International audienceThe role of sphingosine-1 phosphate (S1P) in leukocyte trafficking has been well deciphered in mice but remains largely unaddressed in humans. In this study, we assessed the ex vivo response to S1P of primary human T cell subsets. We found that tonsil but not blood leukocytes were responsive to S1P gradients, suggesting that T cell responsiveness is regulated during their recirculation in vivo. Tonsil naive T cells were readily chemoattracted by S1P in an FTY720-sensitive, S1PR1-dependent manner. Surprisingly, S1P had the opposite effect on effector memory T cells, resident memory T cells, and recently activated T cells, inhibiting their spontaneous or chemokine-induced migration. This inhibition was also more pronounced for CD4 T cells than for CD8 T cell subsets, and was dependent on S1PR2, as shown using the S1PR2 antagonist JTE-013. S1PR1 was progressively downregulated during T cell differentiation whereas S1PR2 expression remained stable. Our results suggest that the ratio between S1PR1 and S1PR2 governs the migratory behavior of T cell subsets. They also challenge previous models of the role of S1P in lymphocyte recirculation and suggest that S1P promotes retention of memory T cell subsets in secondary lymphoid organs, via S1PR2

Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients A multicenter study

Copyright © 2016 The Authors. This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/μL (uVL, P = 0.069) and 480 to 830/μL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.Financial support was provided by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (ISCIII-RETIC RD06/006; RD12/0017/0035, and RD12/0017/0037) and FIPSE (grant number: 36-0910-10). This work has been also supported by grants from Instituto de Salud Carlos III (Ref. MPY 1039/14 to VB). CP is supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT) (grant number SFRH/BPD/77448/2011, part of the EDCTP2 program supported by the European Union). VB is supported by the Miguel Servet program run by the Fondo de Investigación Sanitaria (ISCIII) (grant number CP13/00098).info:eu-repo/semantics/publishedVersio

Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients: A multicenter study

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/μL (uVL, P = 0.069) and 480 to 830/μL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.Financial support was provided by the Instituto de Salud Carlos III through the Red Temática de Investigación Cooperativa en Sida (ISCIII-RETIC RD06/006; RD12/0017/0035, and RD12/0017/0037) and FIPSE (grant number: 36-0910-10). This work has been also supported by grants from Instituto de Salud Carlos III (Ref. MPY 1039/14 to VB). CP is supported by the Portuguese Fundação para a Ciência e Tecnologia (FCT) (grant number SFRH/BPD/77448/2011, part of the EDCTP2 program supported by the European Union). VB is supported by the Miguel Servet program run by the Fondo de Investigación Sanitaria (ISCIII) (grant number CP13/00098).N

Off-label use of rilpivirine in combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA ≥ 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/μL (uVL, P = 0.069) and 480 to 830/μL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children