Sophie Morange

Phenotypic determinants of uncontrolled asthma

BACKGROUND Although uncontrolled asthma remains frequent, determinants of asthma control are poorly studied. OBJECTIVES The aim was to estimate the distribution and the phenotypic characteristics of asthma control in 2 groups of subjects defined by the use of inhaled corticosteroids (ICS) in the past 12 months, in the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). METHODS Five hundred one adult current patients with asthma who participated in the follow-up of the EGEA study were included. Asthma control was assessed from survey questions reflecting asthma control, as defined in the 2006 Global Initiative for Asthma guidelines. The factors analyzed were age, sex, educational level, body mass index, active and passive smoking, sensitization to aeroallergens, total IgE, rhinitis, chronic cough/phlegm, and age at asthma onset. Analyses were stratified according to ICS use. RESULTS Uncontrolled asthma was more frequent in ICS users (27.6%, 35.0%, and 37.4% with controlled, partly-controlled, and uncontrolled asthma respectively) compared with non-ICS users (60.0%, 23.9%, and 16.1%, respectively). In ICS users, chronic cough or phlegm and female sex were independently and significantly related to uncontrolled asthma. In non-ICS users, high total IgE and sensitization to molds were associated with uncontrolled asthma. Smoking and rhinitis were not associated with asthma control. CONCLUSION Optimal asthma control remained unachieved in the majority of patients with asthma in this study. Factors associated with uncontrolled asthma were different in ICS users (chronic cough/phlegm, female sex) and non-ICS users (high total IgE and sensitization to molds).

Differential effect of dietary antioxidant classes (carotenoids, polyphenols, vitamins C and E) on lutein absorption

Lutein is assumed to protect the human retina from blue light and oxidative stress and diminish the incidence of age-related macular degeneration. This antioxidant is commonly ingested with other dietary antioxidants. The aim of the present study was to assess whether the main dietary antioxidants, i.e. carotenoids, polyphenols and vitamins C and E, affect lutein absorption. We measured the effect of adding a mixture of antioxidants (500 mg vitamin C, 67 mg (100 IU) vitamin E and 1 g polyphenols) to a lutein-containing meal (18 mg) on the postprandial lutein response in the chylomicron-rich fraction in eight healthy men. Lutein response was weakest (-23 %; P=0 x 07) after ingestion of the meal containing antioxidants (21 x 9 (sem 4 x 6) v. 28 x 4 (sem 7 x 2) nmol x h/l). To assess the effect of each class of antioxidants and potential interactions, we subsequently evaluated the effect of various combinations of antioxidants on lutein uptake by human intestinal Caco-2 TC-7 cells. A full factorial design showed that both a mixture of polyphenols (gallic acid, caffeic acid, (+)-catechin and naringenin) and a mixture of carotenoids (lycopene plus beta-carotene) significantly (P<0 x 05) impaired lutein uptake by (-10 to-30 %), while vitamins C and E had no significant effect. Subsequent experiments showed that the aglycone flavanone naringenin was the only polyphenol responsible for the effect of the polyphenol mixture, and that the carotenoid effect was not carotenoid species-dependent. Taken together, the present results suggest that lutein absorption is not markedly affected by physiological concentrations of vitamins C and E but can be impaired by carotenoids and naringenin

Infection with hepatitis E virus in kidney transplant recipients in southeastern France

Hepatitis E virus (HEV) is an emerging cause of acute hepatitis in Europe, particularly in southern France, and HEV is a new causative agent of chronic hepatitis and cirrhosis in immunocompromised patients. However, the data regarding HEV infection after kidney transplantation are still scarce with respect to the clinical issues that have been raised, and no study has specifically focused on kidney transplant recipients. This study described the clinical features and outcomes of HEV infections in a cohort of kidney transplant recipients living in southeastern France. The epidemiological, clinical, and virological characteristics of HEV infections diagnosed by PCR over a 53‐month period were retrospectively analyzed in a cohort of 1,350 kidney transplant recipients monitored at the Marseille University Hospital. Sixteen HEV infections were diagnosed, all of which were autochthonous and involved genotype 3 viruses (HEV‐3). Chronic infections occurred in 80% of these patients and resolved in half of the cases after a median time of 39 months. The rate of HEV clearance was 54% after a decrease in the dose of immunosuppressants. One patient developed liver cirrhosis 14 months after infection and experienced acute rejection after a decrease in the dose of immunosuppressants. Autochthonous HEV‐3 infections in kidney transplant recipients progress to chronicity in most cases and might be complicated by early liver cirrhosis. Chronic HEV infection can resolve following the reduction of immunosuppressive therapy, but ribavirin may be required if reduction of the immunosuppressant dose is not associated with HEV clearance or is inappropriate for the patient management. J. Med. Virol. 85:462–471, 2013.

A Pilot Study Comparing Furosemide and Hydrochlorothiazide in Patients With Hypertension and Stage 4 or 5 Chronic Kidney Disease

Furosemide is the diuretic of choice for the treatment of hypertension in chronic kidney disease but the adaptative changes in the distal nephron may decrease its efficacy. Hydrochlorothiazide is not believed to be efficient in this setting. In a randomized, double‐blind, cross‐over trial, 23 patients with hypertension and stage 4 or 5 chronic kidney disease received long‐acting furosemide (60 mg) and hydrochlorothiazide (25 mg) for 3 months and then both diuretics for 3 months. Sodium and chloride fractional excretions were measured after 3 months of each diuretic and then after their association. A trend towards an increase in the fractional excretion of sodium and chloride was observed with furosemide and hydrochlorothiazide (P=not significant). The association of the two diuretics increased the fractional excretions of sodium and chloride from 3.4±1.8 to 4.9±2.8 and from 3.8±2.0 to 6.0±3.1, respectively (P<.05). Furosemide and hydrochlorothiazide decreased mean blood pressure by the same extent. The association of the two diuretics was more efficient on blood pressure. There were no differences between furosemide and hydrochlorothiazide with respect to natriuresis and blood pressure control in patients with hypertension and chronic kidney disease.

Interindividual variability of lutein bioavailability in healthy men: characterization, genetic variants involved, and relation with fasting plasma lutein concentration

BACKGROUND Lutein accumulates in the macula and brain, where it is assumed to play physiologic roles. The bioavailability of lutein is assumed to display a high interindividual variability that has been hypothesized to be attributable, at least partly, to genetic polymorphisms. OBJECTIVES We characterized the interindividual variability in lutein bioavailability in humans, assessed the relation between this variability and the fasting blood lutein concentration, and identified single nucleotide polymorphisms (SNPs) involved in this phenomenon. DESIGN In a randomized, 2-way crossover study, 39 healthy men consumed a meal that contained a lutein supplement or the same meal for which lutein was provided through a tomato puree. The lutein concentration was measured in plasma chylomicrons isolated at regular time intervals over 8 h postprandially. Multivariate statistical analyses were used to identify a combination of SNPs associated with the postprandial chylomicron lutein response (0-8-h area under the curve). A total of 1785 SNPs in 51 candidate genes were selected. RESULTS Postprandial chylomicron lutein responses to meals were very variable (CV of 75% and 137% for the lutein-supplement meal and the meal with tomato-sourced lutein, respectively). Postprandial chylomicron lutein responses measured after the 2 meals were positively correlated (r = 0.68, P < 0.0001) and positively correlated to the fasting plasma lutein concentration (r = 0.51, P < 0.005 for the lutein-supplement-containing meal). A significant (P = 1.9 × 10(-4)) and validated partial least-squares regression model, which included 29 SNPs in 15 genes, explained most of the variance in the postprandial chylomicron lutein response. CONCLUSIONS The ability to respond to lutein appears to be, at least in part, genetically determined. The ability is explained, in large part, by a combination of SNPs in 15 genes related to both lutein and chylomicron metabolism. Finally, our results suggest that the ability to respond to lutein and blood lutein status are related. This trial was registered at clinicaltrials.gov as NCT02100774.

Plasma Xanthine Oxidase Activity Is Predictive of Cardiovascular Disease in Patients with Chronic Kidney Disease, Independently of Uric Acid Levels

Background: Chronic kidney disease (CKD) is associated with increased cardiovascular morbidity and mortality. Oxidative stress seems to play a pivotal role in this process, and purine metabolism may be involved in CKD-related oxidative stress. Xanthine oxidase (XO) is an enzyme involved in purine metabolism and is also responsible for the production of reactive oxygen species. Methods: This prospective study aimed to analyze the relation between plasma dosages of molecules involved in redox balance, purine metabolism and cardiovascular events in patients with non-diabetic CKD stages 3-5 or on chronic hemodialysis (HD). CKD (n = 51) and HD (n = 50) patients were compared to matched healthy controls (n = 38) and followed-up for 3 years. Results: Both CKD and HD patients had decreased plasma levels of antioxidants (selenium, zinc, vitamin C). HD patients had decreased levels of the antioxidant enzyme superoxide dismutase and increased levels of oxidation products (ischemia-modified albumin, malondialdehyde [MDA]). The following substrates and enzymes involved in purine metabolism were increased in the HD cohort: adenosine, adenosine deaminase and the pro-oxidant XO. XO activity was negatively correlated with super oxide dismutase and positively with MDA. Interestingly, XO activity was an independent predictor of cardiovascular events in CKD and HD patients, regardless of uric acid levels. Uric acid was not predictive of events. Conclusion: This highlights a possible role of XO itself in CKD-related cardiovascular disease (CVD) and raises the hypothesis that beneficial effects observed with XO inhibitors on CVD in CKD may also be due to the reduction of oxidative stress.

Fractalkine Expression Induces Endothelial Progenitor Cell Lysis by Natural Killer Cells

Background Circulating CD34+ cells, a population that includes endothelial progenitors, participate in the maintenance of endothelial integrity. Better understanding of the mechanisms that regulate their survival is crucial to improve their regenerative activity in cardiovascular and renal diseases. Chemokine-receptor cross talk is critical in regulating cell homeostasis. We hypothesized that cell surface expression of the chemokine fractalkine (FKN) could target progenitor cell injury by Natural Killer (NK) cells, thereby limiting their availability for vascular repair. Methodology/Principal Findings We show that CD34+-derived Endothelial Colony Forming Cells (ECFC) can express FKN in response to TNF-α and IFN-γ inflammatory cytokines and that FKN expression by ECFC stimulates NK cell adhesion, NK cell-mediated ECFC lysis and microparticles release in vitro. The specific involvement of membrane FKN in these processes was demonstrated using FKN-transfected ECFC and anti-FKN blocking antibody. FKN expression was also evidenced on circulating CD34+ progenitor cells and was detected at higher frequency in kidney transplant recipients, when compared to healthy controls. The proportion of CD34+ cells expressing FKN was identified as an independent variable inversely correlated to CD34+ progenitor cell count. We further showed that treatment of CD34+ circulating cells isolated from adult blood donors with transplant serum or TNF-α/IFN-γ can induce FKN expression. Conclusions Our data highlights a novel mechanism by which FKN expression on CD34+ progenitor cells may target their NK cell mediated killing and participate to their immune depletion in transplant recipients. Considering the numerous diseased contexts shown to promote FKN expression, our data identify FKN as a hallmark of altered progenitor cell homeostasis with potential implications in better evaluation of vascular repair in patients.

Population pharmacokinetics analysis of mycophenolic acid in adult kidney transplant patients with chronic graft dysfunction.

The aim of this study is to develop a population pharmacokinetic model for total and free mycophenolic acid (MPA) in adult kidney transplant patients with chronic graft dysfunction to understand the contribution of potentially relevant covariates to the inter- and the intraindividual variability of MPA in these patients. Twenty patients received mycophenolate mofetil orally up to 1 g twice daily were enrolled in this prospective pharmacokinetic study. Two hundred twenty-nine total and 257 free concentration-time points were determined using reversed-phase high-performance liquid chromatography/ultraviolet at 21 days and 6 months after initiation of mycophenolate mofetil therapy. Data were analyzed using nonlinear mixed effects modeling. A two-compartment model, with zero-order input and first-order elimination from the central compartment, which combined total and free concentration, was selected. Intersubject variability (ISV) was estimated on the clearance, central volume of distribution, and intercompartmental clearance. Only body weight (WT, kg), occasion, and albumin concentration (mg/L) were kept as covariates in the final model. The population pharmacokinetic parameters were: clearance, 0.27 × WT (L/h) on Day 21 and 0.233 × WT (L/h) at 6 months (ISV, 51%; interoccasion variability, 47%); central distribution volume, 47.6 L (ISV, 31%); intercompartmental clearance, 33.1 L/h (ISV, 128%); peripheral distribution volume, 724 L; duration of infusion, 0.64 (hours), and binding capacity, 0.0012 L/mg. The multiple regression analysis between free and total MPA concentration led to the following model: free MPA concentration (mg/L) = 0.31 + 0.02 total MPA concentration (mg/L) - 0.007 albumin (g/L). The large inter- and intravariability of MPA raises questions about the value of the use of therapeutic monitoring and limited sampling strategies as currently practiced. Moreover, none of the data presented here could justify measurement of free concentration for therapeutic drug monitoring.

Antibody-Dependent NK Cell Activation Is Associated with Late Kidney Allograft Dysfunction and the Complement-Independent Alloreactive Potential of Donor-Specific Antibodies

Although kidney transplantation remains the best treatment for end-stage renal failure, it is limited by chronic humoral aggression of the graft vasculature by donor-specific antibodies (DSAs). The complement-independent mechanisms that lead to the antibody-mediated rejection (ABMR) of kidney allografts remain poorly understood. Increasing lines of evidence have revealed the relevance of natural killer (NK) cells as innate immune effectors of antibody-dependent cellular cytotoxicity (ADCC), but few studies have investigated their alloreactive potential in the context of solid organ transplantation. Our study aimed to investigate the potential contribution of the antibody-dependent alloreactive function of NK cells to kidney graft dysfunction. We first conducted an observational study to investigate whether the cytotoxic function of NK cells is associated with chronic allograft dysfunction. The NK-Cellular Humoral Activation Test (NK-CHAT) was designed to evaluate the recipient and antibody-dependent reactivity of NK cells against allogeneic target cells. The release of CD107a/Lamp1+ cytotoxic granules, resulting from the recognition of rituximab-coated B cells by NK cells, was analyzed in 148 kidney transplant recipients (KTRs, mean graft duration: 6.2 years). Enhanced ADCC responsiveness was associated with reduced graft function and identified as an independent risk factor predicting a decline in the estimated glomerular filtration rate over a 1-year period (hazard ratio: 2.83). In a second approach, we used the NK-CHAT to reveal the cytotoxic potential of circulating alloantibodies in vitro. The level of CD16 engagement resulting from the in vitro recognition of serum-coated allogeneic B cells or splenic cells was further identified as a specific marker of DSA-induced ADCC. The NK-CHAT scoring of sera obtained from 40 patients at the time of transplant biopsy was associated with ABMR diagnosis. Our findings indicate that despite the administration of immunosuppressive treatments, robust ADCC responsiveness can be maintained in some KTRs. Because it evaluates both the Fab recognition of alloantigens and Fc-driven NK cell activation, the NK-CHAT represents a potentially valuable tool for the non-invasive and individualized evaluation of humoral risk during transplantation.

A Combination of Single-Nucleotide Polymorphisms Is Associated with Interindividual Variability in Cholecalciferol Bioavailability in Healthy Men

BACKGROUND Most people require dietary vitamin D to achieve the recommended concentration of 25-hydroxyvitamin D [25(OH)D] in the blood. However, the response to vitamin D supplementation is highly variable among individuals. OBJECTIVE We assessed whether the variability in cholecalciferol bioavailability was associated with single-nucleotide polymorphisms (SNPs) in candidate genes. METHODS In a single-group design, 39 healthy adult men with a mean ± SD age of 33 ± 2 y and mean ± SD body mass index (in kg/m2) of 22.9 ± 0.3 were genotyped with the use of whole-genome microarrays. After an overnight fast, plasma 25(OH)D status was measured, and the subjects then consumed a meal that provided 5 mg cholecalciferol as a supplement. Plasma chylomicron cholecalciferol concentration was measured over 8 h, and cholecalciferol response was assessed by calculating the postprandial area under the curve. Partial least squares regression was used to test the association of SNPs in or near candidate genes (61 genes representing 3791 SNPs) with the postprandial cholecalciferol response. RESULTS The postprandial chylomicron cholecalciferol concentration peaked at 5.4 h. The cholecalciferol response was extremely variable among individuals (CV: 47%). It correlated with the chylomicron triglyceride (TG) response (r = 0.60; P < 0.001) but not with the fasting plasma 25(OH)D concentration (r = 0.04; P = 0.83). A significant (P = 1.32 × 10-4) partial least squares regression model that included 17 SNPs in 13 genes (including 5 that have been associated with chylomicron TG response) was associated with the variance in the cholecalciferol response. CONCLUSION In healthy men, there is a high interindividual variability in cholecalciferol bioavailability that is associated with a combination of SNPs located in or near genes involved in both vitamin D and lipid metabolism. This trial was registered at clinicaltrials.gov as NCT02100774.