Microcirculation in chronic kidney disease : from injury targets to potential therapeutics

Chronic kidney disease (CKD) is a major public health problem worldwide, and patients with end-stage kidney disease (ESKD) are at increased risk of developing cardiovascular complications. Small artery dysfunction is a common feature of CKD, which contributes to the development of early vascular ageing (EVA) and cardiovascular complications. The exact mechanisms of how small artery dysfunction contributes to these complications are not fully understood. The ultimate goal of this PhD thesis is to gain a better understanding on how small artery dysfunction contributes to EVA and cardiovascular risk in the uremic environment, and to define specific targets for potential therapeutic benefit. The methodological approaches involve both ex vivo and in vivo investigations, including biochemical marker measurements, immuno staining, as well as isolated small artery bioassays and wire myography technique together with EndoPAT to assess peripheral arterial tone. In Paper I we investigated both in vivo and ex vivo functional properties (reactive hyperemia index [RHI], contractility, vasodilatory, stiffness) of small resistance arteries from ESKD patients and non-CKD controls. We also investigated ex vivo effects of trimethylamine Noxide (TMAO), phenylacetyl glutamine (PAG) and extracellular vesicles (EVs) from CKD-5 patients, as well as pharmacological interventions using senolytics. We assessed markers of senescence, calcification, endothelial function, and oxidative stress; these data were also correlated with functional and structural properties of resistance arteries. We observed that the uremic environment influences vascular function by changing the contribution of endotheliumderived factors (i.e. reduced nitric oxide and increased endothelium derived hyperpolarization factor) and increasing vascular stiffness in patients with ESKD; these events were further modulated by inflammation, TMAO, PAG and EVs. Moreover, the vasculature of ESKD patients was characterized by hallmarks of EVA –presence of the senescence signature, microcalcification, reduced anti-oxidant control, and decreased contractile markers which might confer the development of cardiovascular complications in this specific patient group. We also showed that senolytics could be used to target senescent cells. As Paper I comprehensively phenotypes the microcirculation from ESKD patients, this study serves as a backbone for the overall thesis. Paper II, a complementary study of Paper I, adds more insight into endothelial function and vascular structure biology in respect to different amino acids (AA) and their metabolites. New findings include impaired AA metabolism with decreased biopterin BH4/BH2 ratio in CKD, as well as elevated asymmetric dimethylarginine levels that were associated with higher vascular stiffness and reduced NO contribution. In Paper III, we investigated differences in the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) receptors in resistance arteries and subcutaneous adipose tissue, alongside circulating soluble ACE2 levels in female and male ESKD patients versus non-CKD controls. Our results demonstrated that soluble ACE2 levels were higher in ESKD patients. In addition, ACE2 tissue expression was higher in ESKD patients with a higher prevalence in male subjects and was present in both the endothelium and VSMCs from arteries in peripheral microcirculation. The aim of Paper IV was to better understand the role of prostaglandin contribution to vasoactive properties and characterize the effects of microsomal prostaglandin E synthase-1 (mPGES-1) inhibition in the microvasculature of CKD patients. A significant reduction in adrenergic vasoconstriction and improvement in relaxation was observed following mPGES-1 inhibition. Based on our findings, it can be inferred that mPGES-1 inhibition has additional vasoactive effects in the human microcirculation beyond the shunting to prostacyclin (PGI2) pathway, i.e. a reduction in the levels of local prostaglandin E2 (PGE2), as well as influencing other vascular factors. This indicates the interaction of several pathways after mPGES-1 inhibition. The findings of this thesis provide valuable insights into the mechanisms underlying small artery maintenance and dysfunction in ESKD patients and identify potential therapeutic targets for improving vascular function in this patient population

Senescent cells in early vascular ageing and bone disease of chronic kidney disease—a novel target for treatment

Together with bone-mineral disorders, premature vascular ageing is a common feature of the uremic phenotype. A detailed understanding of mechanisms involved remains unclear and warrants further research. Available treatment options for end stage renal disease are principally dialysis and organ transplantation, as other treatment alternatives have proven insufficient. Chronic kidney disease (CKD) has been proposed as a model of early vascular and bone ageing, with accumulating evidence supporting the contribution of cellular senescence and the senescence-associated secretory phenotype (SASP) to cardiovascular pathology in CKD. Correspondingly, novel therapies based around the use of senolytic compounds and nuclear factor-erythroid-2-related factor 2 (Nrf2) agonists, have been suggested as attractive novel treatment options. In this review, we detail the contribution of the uremic environment to these processes underpinning ageing and how these relate to vascular health

Inflammation and premature ageing in chronic kidney disease

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)−kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23−klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them

Nrf2 in early vascular ageing: calcification, senescence and therapy

Under normal physiological conditions, free radical generation and antioxidant defences are balanced, and reactive oxygen species (ROS) usually act as secondary messengers in a plethora of biological processes. However, when this balance is impaired, oxidative stress develops due to imbalanced redox homeostasis resulting in cellular damage. Oxidative stress is now recognized as a trigger of cellular senescence, which is associated with multiple chronic 'burden of lifestyle' diseases, including atherosclerosis, type-2 diabetes, chronic kidney disease and vascular calcification; all of which possess signs of early vascular ageing. Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in conditions characterized by oxidative stress and inflammation. Recent evidence suggests that activation of Nrf2 may be beneficial in protecting against vascular senescence and calcification. Both natural and synthetic Nrf2 agonists have been introduced as promising drug classes in different phases of clinical trials. However, overexpression of the Nrf2 pathway has also been linked to tumorigenesis, which highlights the requirement for further understanding of pathways involving Nrf2 activity, especially in the context of cellular senescence and vascular calcification. Therefore, comprehensive translational pre-clinical and clinical studies addressing the targeting capabilities of Nrf2 agonists are urgently required. The present review discusses the impact of Nrf2 in senescence and calcification in early vascular ageing, with focus on the potential clinical implications of Nrf2 agonists and non-pharmacological Nrf2 therapeutics

Effects of a Synbiotic on Plasma Immune Activity Markers and Short-Chain Fatty Acids in Children and Adults with ADHD—A Randomized Controlled Trial

Synbiotic 2000, a pre + probiotic, reduced comorbid autistic traits and emotion dysregulation in attention deficit hyperactivity disorder (ADHD) patients. Immune activity and bacteria-derived short-chain fatty acids (SCFAs) are microbiota–gut–brain axis mediators. The aim was to investigate Synbiotic 2000 effects on plasma levels of immune activity markers and SCFAs in children and adults with ADHD. ADHD patients (n = 182) completed the 9-week intervention with Synbiotic 2000 or placebo and 156 provided blood samples. Healthy adult controls (n = 57) provided baseline samples. At baseline, adults with ADHD had higher pro-inflammatory sICAM-1 and sVCAM-1 and lower SCFA levels than controls. Children with ADHD had higher baseline sICAM-1, sVCAM-1, IL-12/IL-23p40, IL-2Rα, and lower formic, acetic, and propionic acid levels than adults with ADHD. sICAM-1, sVCAM-1, and propionic acid levels were more abnormal in children on medication. Synbiotic 2000, compared to placebo, reduced IL-12/IL-23p40 and sICAM-1 and increased propionic acid levels in children on medication. SCFAs correlated negatively with sICAM-1 and sVCAM-1. Preliminary human aortic smooth-muscle-cell experiments indicated that SCFAs protected against IL-1β-induced ICAM-1 expression. These findings suggest that treatment with Synbiotic 2000 reduces IL12/IL-23p40 and sICAM-1 and increases propionic acid levels in children with ADHD. Propionic acid, together with formic and acetic acid, may contribute to the lowering of the higher-than-normal sICAM-1 levels

Contrôleur robuste d'un vibreur pour la qualification mécanique des satellites

The aim of this thesis is to eliminate the beating phenomenon of the vibration testing systems during the mechanical qualification of the spacecraft. Mechanical qualification tests consist in applying, at the spacecraft interface, a sine sweep acceleration at given frequencies and magnitudes, depending on the launcher's requirements. However, the shaker control used for this qualification is often unsatisfying in terms of tracking performance in the neighborhood of spacecraft's structural modes and tank modes. Inopportune aborts may also happen during tests due to unacceptable overshoots. The reason for these troubles is the nonlinear control algorithm currently used, inappropriate for spacecrafts with very lightly damped vibrational modes. Therefore, the proposed work consists in developing a control strategy able to avoid the instabilities of the composite model, which includes shaker, interface, and spacecraft chain.Following a preliminary study of the phenomenon of oscillation and current literature on the topic of active vibration control, the research is conducted, moving the current control architecture towards a robust control strategy. The vibration testing system indeed imposes strict performance in terms of dynamic tracking for a very large frequency range. The developed robust control strategy also needs to overcome the usual conservatism noticed when the plant dynamics contain lightly damped modes.Firstly, a feasibility study conducted on a simplified lightly-damped system highlights the elimination of vibration via robust control. Then an identified model of a real commercial satellite is used to demonstrate the superior performance of the proposed control architecture. Finally, in order to overcome one of the main challenges related to the sensitivity of the robust control against any modal parameter variation, a reformulation of the control structure allows the desensitization of the robust control against these kinds of variations in the system.This work ends with a model in the loop architecture of the vibration testing system in order to validate the control study via both time and frequency domain simulations known as the virtual shaker test. In the frame of the used industrial hardware architecture, the newly defined strategy formulation allows the implementation based on the existing hardware and software components.L'objectif de cette thèse est d'éliminer le phénomène de battement du système d'essais vibratoires lors de la qualification mécanique de satellite. Les essais en qualification mécanique consistent à appliquer, à l'interface du satellite, une accélération résultant d'un balayage sinusoïdal à des fréquences et amplitudes données, en fonction des besoins du lanceur. Cependant, la structure de la commande utilisée pour cette qualification est souvent non satisfaisante en termes de performances de suivi de la référence au voisinage des modes structuraux et des modes réservoir du satellite. Des interruptions peuvent également se produire pendant les tests en raison de dépassements inacceptables. En effet, l'algorithme de commande non linéaire actuellement utilisé s'avère peu adapté aux dynamiques ayant des modes de vibration très peu amortis. Le travail proposé consiste donc à développer une stratégie de contrôle capable d'éviter les instabilités du modèle composite qui comprend l'actionneur, l'interface et le satellite. Après une étude portant sur le phénomène d'oscillation et sur la littérature dans le domaine du contrôle actif de vibrations, la recherche a été menée avec l'objectif de faire évoluer l'architecture de commande actuelle vers une stratégie de commande robuste. Le système d'essais en vibration nécessite en effet de satisfaire des performances de précision strictes en suivi dynamique pour une très large bande de fréquence. De plus, la stratégie développée doit s'affranchir du conservatisme des commandes robustes habituellement constaté lorsque la dynamique du système contient des modes faiblement amortis.Dans un premier temps, une étude de faisabilité sur un système simplifié faiblement amorti montre la suppression des vibrations du système via une commande robuste. Ensuite, un modèle identifié d'un satellite commercial réel est utilisé pour démontrer les performances supérieures obtenues par l'architecture de commande proposée. Finalement, afin de surmonter l'un des principaux défis lié à la sensibilité de la commande robuste vis-à-vis de toute variation des paramètres modaux, une reformulation de la structure de commande permet la désensibilisation de la commande robuste face à ce type de variations paramétriques.Cette étude se termine par un Model In the Loop (MIL ) du système d'essai de vibration afin de valider l'ensemble des travaux via des simulations dans les domaines temporel et fréquentiel, connus sous le nom d'essai en vibration virtuel. Une formulation adaptée de la stratégie de commande développée au cadre de l'architecture matérielle industrielle utilisée permet son implémentation avec des composants matériels et logiciels existants

Contrôleur robuste d'un vibreur pour la qualification mécanique des satellites

The aim of this thesis is to eliminate the beating phenomenon of the vibration testing systems during the mechanical qualification of the spacecraft. Mechanical qualification tests consist in applying, at the spacecraft interface, a sine sweep acceleration at given frequencies and magnitudes, depending on the launcher's requirements. However, the shaker control used for this qualification is often unsatisfying in terms of tracking performance in the neighborhood of spacecraft's structural modes and tank modes. Inopportune aborts may also happen during tests due to unacceptable overshoots. The reason for these troubles is the nonlinear control algorithm currently used, inappropriate for spacecrafts with very lightly damped vibrational modes. Therefore, the proposed work consists in developing a control strategy able to avoid the instabilities of the composite model, which includes shaker, interface, and spacecraft chain.Following a preliminary study of the phenomenon of oscillation and current literature on the topic of active vibration control, the research is conducted, moving the current control architecture towards a robust control strategy. The vibration testing system indeed imposes strict performance in terms of dynamic tracking for a very large frequency range. The developed robust control strategy also needs to overcome the usual conservatism noticed when the plant dynamics contain lightly damped modes.Firstly, a feasibility study conducted on a simplified lightly-damped system highlights the elimination of vibration via robust control. Then an identified model of a real commercial satellite is used to demonstrate the superior performance of the proposed control architecture. Finally, in order to overcome one of the main challenges related to the sensitivity of the robust control against any modal parameter variation, a reformulation of the control structure allows the desensitization of the robust control against these kinds of variations in the system.This work ends with a model in the loop architecture of the vibration testing system in order to validate the control study via both time and frequency domain simulations known as the virtual shaker test. In the frame of the used industrial hardware architecture, the newly defined strategy formulation allows the implementation based on the existing hardware and software components.L'objectif de cette thèse est d'éliminer le phénomène de battement du système d'essais vibratoires lors de la qualification mécanique de satellite. Les essais en qualification mécanique consistent à appliquer, à l'interface du satellite, une accélération résultant d'un balayage sinusoïdal à des fréquences et amplitudes données, en fonction des besoins du lanceur. Cependant, la structure de la commande utilisée pour cette qualification est souvent non satisfaisante en termes de performances de suivi de la référence au voisinage des modes structuraux et des modes réservoir du satellite. Des interruptions peuvent également se produire pendant les tests en raison de dépassements inacceptables. En effet, l'algorithme de commande non linéaire actuellement utilisé s'avère peu adapté aux dynamiques ayant des modes de vibration très peu amortis. Le travail proposé consiste donc à développer une stratégie de contrôle capable d'éviter les instabilités du modèle composite qui comprend l'actionneur, l'interface et le satellite. Après une étude portant sur le phénomène d'oscillation et sur la littérature dans le domaine du contrôle actif de vibrations, la recherche a été menée avec l'objectif de faire évoluer l'architecture de commande actuelle vers une stratégie de commande robuste. Le système d'essais en vibration nécessite en effet de satisfaire des performances de précision strictes en suivi dynamique pour une très large bande de fréquence. De plus, la stratégie développée doit s'affranchir du conservatisme des commandes robustes habituellement constaté lorsque la dynamique du système contient des modes faiblement amortis.Dans un premier temps, une étude de faisabilité sur un système simplifié faiblement amorti montre la suppression des vibrations du système via une commande robuste. Ensuite, un modèle identifié d'un satellite commercial réel est utilisé pour démontrer les performances supérieures obtenues par l'architecture de commande proposée. Finalement, afin de surmonter l'un des principaux défis lié à la sensibilité de la commande robuste vis-à-vis de toute variation des paramètres modaux, une reformulation de la structure de commande permet la désensibilisation de la commande robuste face à ce type de variations paramétriques.Cette étude se termine par un Model In the Loop (MIL ) du système d'essai de vibration afin de valider l'ensemble des travaux via des simulations dans les domaines temporel et fréquentiel, connus sous le nom d'essai en vibration virtuel. Une formulation adaptée de la stratégie de commande développée au cadre de l'architecture matérielle industrielle utilisée permet son implémentation avec des composants matériels et logiciels existants

Contrôleur robuste d'un vibreur pour la qualification mécanique des satellites

L'objectif de cette thèse est d'éliminer le phénomène de battement du système d'essais vibratoires lors de la qualification mécanique de satellite. Les essais en qualification mécanique consistent à appliquer, à l'interface du satellite, une accélération résultant d'un balayage sinusoïdal à des fréquences et amplitudes données, en fonction des besoins du lanceur. Cependant, la structure de la commande utilisée pour cette qualification est souvent non satisfaisante en termes de performances de suivi de la référence au voisinage des modes structuraux et des modes réservoir du satellite. Des interruptions peuvent également se produire pendant les tests en raison de dépassements inacceptables. En effet, l'algorithme de commande non linéaire actuellement utilisé s'avère peu adapté aux dynamiques ayant des modes de vibration très peu amortis. Le travail proposé consiste donc à développer une stratégie de contrôle capable d'éviter les instabilités du modèle composite qui comprend l'actionneur, l'interface et le satellite. Après une étude portant sur le phénomène d'oscillation et sur la littérature dans le domaine du contrôle actif de vibrations, la recherche a été menée avec l'objectif de faire évoluer l'architecture de commande actuelle vers une stratégie de commande robuste. Le système d'essais en vibration nécessite en effet de satisfaire des performances de précision strictes en suivi dynamique pour une très large bande de fréquence. De plus, la stratégie développée doit s'affranchir du conservatisme des commandes robustes habituellement constaté lorsque la dynamique du système contient des modes faiblement amortis.Dans un premier temps, une étude de faisabilité sur un système simplifié faiblement amorti montre la suppression des vibrations du système via une commande robuste. Ensuite, un modèle identifié d'un satellite commercial réel est utilisé pour démontrer les performances supérieures obtenues par l'architecture de commande proposée. Finalement, afin de surmonter l'un des principaux défis lié à la sensibilité de la commande robuste vis-à-vis de toute variation des paramètres modaux, une reformulation de la structure de commande permet la désensibilisation de la commande robuste face à ce type de variations paramétriques.Cette étude se termine par un Model In the Loop (MIL ) du système d'essai de vibration afin de valider l'ensemble des travaux via des simulations dans les domaines temporel et fréquentiel, connus sous le nom d'essai en vibration virtuel. Une formulation adaptée de la stratégie de commande développée au cadre de l'architecture matérielle industrielle utilisée permet son implémentation avec des composants matériels et logiciels existants.The aim of this thesis is to eliminate the beating phenomenon of the vibration testing systems during the mechanical qualification of the spacecraft. Mechanical qualification tests consist in applying, at the spacecraft interface, a sine sweep acceleration at given frequencies and magnitudes, depending on the launcher's requirements. However, the shaker control used for this qualification is often unsatisfying in terms of tracking performance in the neighborhood of spacecraft's structural modes and tank modes. Inopportune aborts may also happen during tests due to unacceptable overshoots. The reason for these troubles is the nonlinear control algorithm currently used, inappropriate for spacecrafts with very lightly damped vibrational modes. Therefore, the proposed work consists in developing a control strategy able to avoid the instabilities of the composite model, which includes shaker, interface, and spacecraft chain.Following a preliminary study of the phenomenon of oscillation and current literature on the topic of active vibration control, the research is conducted, moving the current control architecture towards a robust control strategy. The vibration testing system indeed imposes strict performance in terms of dynamic tracking for a very large frequency range. The developed robust control strategy also needs to overcome the usual conservatism noticed when the plant dynamics contain lightly damped modes.Firstly, a feasibility study conducted on a simplified lightly-damped system highlights the elimination of vibration via robust control. Then an identified model of a real commercial satellite is used to demonstrate the superior performance of the proposed control architecture. Finally, in order to overcome one of the main challenges related to the sensitivity of the robust control against any modal parameter variation, a reformulation of the control structure allows the desensitization of the robust control against these kinds of variations in the system.This work ends with a model in the loop architecture of the vibration testing system in order to validate the control study via both time and frequency domain simulations known as the virtual shaker test. In the frame of the used industrial hardware architecture, the newly defined strategy formulation allows the implementation based on the existing hardware and software components