Generation of a human iPS cell line from a patient with retinitis pigmentosa due to EYS mutation

Retinitis pigmentosa (RP) is an inherited retinal degenerative disease. Mutations in EYS have been associated with autosomal recessive RP. The human iPS cell line, CABi002-A, derived from peripheral blood mononuclear cells from a patient carrying a heterozygous double mutation in EYS gene was generated by non-integrative reprogramming technology, using hOCT3/4, hSOX2, hc-MYC and hKLF4 reprogramming factors. Pluripotency and differentiation capacity were assessed by immunocytochemistry and RT-PCR. This iPSC line can be further differentiated towards the affected cells to understand the pathophysiology of the disease and test new therapeutic strategies.Cellex FoundationFundación Progreso y Salu

Severe Leptospirosis with Multiple Organ Failure Successfully Treated by Plasma Exchange and High-Volume Hemofiltration

Background. Leptospirosis is a spirochetal zoonosis with complex clinical features including renal and liver failure. Case report. We report the case of a Swiss fisherman presenting with leptospirosis. After initial improvement, refractory septic shock and severe liver and kidney failure developed. The expected mortality was estimated at 90% with clinical scores. The patient underwent plasma exchanges and high-volume hemofiltration (HVHF) with complete recovery of hepatic and kidney functions. Discussion. Plasma exchanges and HVHF may confer survival benefit on patients with severe leptospirosis, refractory septic shock, and multiple-organ failure

Grief Experiences in Family Caregivers of Children with Autism Spectrum Disorder (ASD)

The main objective of this study was to analyse the experience of grief and feelings of loss in family caregivers of children diagnosed with autism spectrum disorder (ASD), as well as the perceived overload from taking on the primary caregiver role. Twenty family caregivers of children with ASD participated. The family members were assessed using an ad-hoc semi-structured interview that addressed the families' reactions to the diagnosis, implications for daily functioning, and concerns for the immediate and long-term future of their relatives with ASD. The results indicate that family caregivers of children with ASD endure intense and continuous sorrow and grief due to the impact that having and caring for a child with these characteristics has on all aspects of their lives. These data highlight the importance of creating support and intervention programmes and services focused on the feelings and manifestations of ambiguous grief that occur in these family members, in order to improve their well-being and quality of life and reduce caregiver role overload

Determinants and burden of chronic kidney disease in the population-based CoLaus study: a cross-sectional analysis

Background Chronic kidney disease (CKD) represents an increasing health burden. We present the population-based prevalence of CKD and compare the CKD Epidemiology collaboration (CKD-EPI) and modification of diet in renal disease (MDRD) equations to estimate the glomerular filtration rate, using the revised CKD classification with three albuminuria classes. We also explore factors associated with CKD. Methods The Swiss population-based, cross-sectional CoLaus study conducted in Lausanne (2003-2006) included 2810 men and 3111 women aged 35-75. CKD prevalence was assessed using CKD-EPI and MDRD equations and albuminuria estimated by the albumin-to-creatinine ratio in spot morning urine. Multivariate logistic regression was used to analyse determinants of CKD. Results Prevalence [95% confidence interval (CI)] of all stages CKD was 10.0% (9.2-10.8%) with CKD-EPI and 13.8% (12.9-14.6%) with MDRD. Using the revised CKD classification, the prevalence of low-, medium-, high- and very high-risk groups was 90.0, 8.46, 1.18 and 0.35% with CKD-EPI, respectively. With MDRD, the corresponding values were 86.24, 11.86, 1.55 and 0.35%. Using the revised classification, CKD-EPI systematically reclassified people in a lower risk category than MDRD. Age and obesity were more strongly associated with CKD in men [odds ratio (95% CI): 2.23(1.95; 2.56) per 10 years and 3.05(2.08;4.47), respectively] than in women [1.46 (1.29; 1.65) and 1.78 (1.30;2.44), respectively]. Hypertension, type 2 diabetes, serum homocysteine and uric acid were positively independently associated with CKD in men and women. Conclusions One in 10 adults suffers from CKD in the population of Lausanne. CKD-EPI systematically reclassifies people in a lower CKD risk category than MDRD. Serum homocysteine and uric acid levels are associated with CKD independently of classical risk factors such as age, hypertension and diabete

Geospatial Analysis of Sodium and Potassium Intake: A Swiss Population-Based Study.

Inadequate sodium and potassium dietary intakes are associated with major, yet preventable, health consequences. Local public health interventions can be facilitated and informed by fine-scale geospatial analyses. In this study, we assess the existence of spatial clustering (i.e., an unusual concentration of individuals with a specific outcome in space) of estimated sodium (Na), potassium (K) intakes, and Na:K ratio in the Bus Santé 1992-2018 annual population-based surveys, including 22,495 participants aged 20-74 years, residing in the canton of Geneva, using the local Moran's I spatial statistics. We also investigate whether socio-demographic and food environment characteristics are associated with identified spatial clustering, using both global ordinary least squares (OLS) and local geographically weighted regression (GWR) modeling. We identified clear spatial clustering of Na:K ratio, Na, and K intakes. The GWR outperformed the OLS models and revealed spatial variations in the associations between explanatory and outcome variables. Older age, being a woman, higher education, and having a lower access to supermarkets were associated with higher Na:K ratio, while the opposite was seen for having the Swiss nationality. Socio-demographic characteristics explained a major part of the identified clusters. Socio-demographic and food environment characteristics significantly differed between individuals in spatial clusters of high and low Na:K ratio, Na, and K intakes. These findings could guide prioritized place-based interventions tailored to the characteristics of the identified populations

The Urine-to-Plasma Urea Concentration Ratio is associated with eGFR and eGFR decline over time in a population cohort.

BACKGROUND Evaluation of renal function and of factors associated with its decline are important public health issues. Besides markers of glomerular function (e.g., GFR), those of tubular functions are rarely evaluated. Urea, the most abundant urinary solute, is markedly concentrated in urine when compared to plasma. We explored the urine-to-plasma ratio of urea concentrateions (U/P-urea-ratio) as a marker of tubular functions. METHODS We evaluated the relationship of the U/P-urea-ratio with eGFR at baseline in 1043 participants (48±17y) from the SKIPOGH population-based cohort, using mixed regression. In 898 participants, we assessed the relation between U/P-urea-ratio and renal function decline between two study waves 3 years apart. We studied U/P ratios for osmolarity, Na, K, uric acid for comparison. RESULTS In a transversal study at baseline, eGFR was positively associated with U/P-urea-ratio (βscaled = 0.08, 95%CI[0.04;0.13]) but not with the U/P ratio of osmolarity. Considering separately participants with renal function > or ≤ 90 ml/minx1.73m2, this association was observed only in those with reduced renal function. In the longitudinal study, eGFR declined at a mean rate of 1.2 ml/min per year. A significant association was observed between baseline U/P-urea-ratio and eGFR decline (βscaled = 0.08, 95%CI[0.01;0.15]). A lower baseline U/P-urea-ratio was associated with a greater eGFR decline. CONCLUSION This study provides evidence that the U/P-urea-ratio is an early marker of kidney function decline in the general adult population. Urea is easy to measure with well-standardized techniques and at low cost. Thus, the U/P-urea-ratio could become an easily available tubular marker for evaluating renal function decline

PhenoExplorer: An Interactive Web-based Platform for Exploring (Epi)Genome-Wide Associations Using a Swiss Population-based Study

The recent advent of high-throughput sequencing technologies has allowed exploring the contribution of thousands of genomic, epigenomic, transcriptomic, or proteomic variants to complex phenotypic traits. Here, we sought to conduct large-scale (Epi)Genome-Wide Association Studies (GWAS/EWAS) to investigate the associations between genomic (Single Nucleotide Polymorphism; SNP) and epigenomic (Cytosine-Phospho-Guanine; CpG) markers, with multiple phenotypic traits in a population-based context. We used data from SKIPOGH, a family- and population-based cohort conducted in the cities of Lausanne, Geneva, and Bern (N=1100). We used 7,577,572 SNPs, 420,444 CpGs, and 825 phenotypes, including anthropometric, clinical, blood, urine, metabolite, and metal measures. GWAS analyses assessed the associations between SNPs and metabolites and metals (N=279), using regression models adjusted for age, sex, recruitment center, and familial structure, whereas EWAS analyses explored the relations between CpGs and 825 phenotypes, additionally adjusting for the seasonality of blood sampling and technical nuisance. Following the implementation of GWAS and EWAS analyses, we developed a web-based platform, PhenoExplorer, aimed at providing an open access to the obtained results. Of the 279 phenotypes included in GWAS, 103 displayed significant associations with 2804 SNPs (2091 unique SNPs) at Bonferroni threshold, whereas 109 of the 825 phenotypes included in EWAS analyses were associated with 4893 CpGs (2578 unique CpGs). All of the obtained GWAS and EWAS results were eventually made available using the in-house built web-based PhenoExplorer platform, with the purpose of providing an open-access to the tested associations. In conclusion, we provide a comprehensive outline of GWAS and EWAS associations performed in a Swiss population-based study. Further, we set up a web-based PhenoExplorer platform with the purpose of contributing to the overall understanding of the role of molecular variants in regulating complex phenotypes

Hypoxia Inducible Factor 1-Alpha (HIF-1 Alpha) Is Induced during Reperfusion after Renal Ischemia and Is Critical for Proximal Tubule Cell Survival

Acute tubular necrosis (ATN) caused by ischemia/reperfusion (I/R) during renal transplantation delays allograft function. Identification of factors that mediate protection and/or epithelium recovery could help to improve graft outcome. We studied the expression, regulation and role of hypoxia inducible factor 1-alpha (HIF-1 α), using in vitro and in vivo experimental models of I/R as well as human post-transplant renal biopsies. We found that HIF-1 α is stabilized in proximal tubule cells during ischemia and unexpectedly in late reperfusion, when oxygen tension is normal. Both inductions lead to gene expression in vitro and in vivo. In vitro interference of HIF-1 α promoted cell death and in vivo interference exacerbated tissue damage and renal dysfunction. In pos-transplant human biopsies, HIF-1 α was expressed only in proximal tubules which exhibited normal renal structure with a significant negative correlation with ATN grade. In summary, using experimental models and human biopsies, we identified a novel HIF-1 α induction during reperfusion with a potential critical role in renal transplant

New Carcliovascular risk factors and kidney: a population-based approach

Patients with chrome kidney disease (CK.D) are prone to suffcr from cardiovascular (CV) diseases and die from CV causes at early stages, before even reaching end-stage renal disease. Age, sex, smoking, hypertension, diabètes, dyslipidemia, positive family history are considered as classical CV risk factors. However, in CKD patients other factors seem to influence CV risk. Therefore the aim, of tins PhD thesis was to analyze the rôle of “novel biomarkers” on cardiovascular risk or protection, including a spécifie focus on selected nutritional factors (salt, vitamin K and caffeine), and their link to renal and vascular function in two Swiss population-based studies. In the First Chapter, I présent how Uromodulin, a protein produced by the kidney. is related to kidney mass. 1 show the link between this protein and blood pressure as well as CV risk through its effect of sodium absorption and increase in salt-sensitivity. In the second Chapter, the effect of salt intake on the kidneys is investigated. I establish that high sodium intake, corresponding to high urinary excrétion, seem to accelerate the ageing décliné of rénal function. Part of this effect, could be mediated by an effect of sait on kidney microvasculature. as we observe that higher sodium excrétion is associated with rénal résistive index (RRI) increase but not central puise wave velocity (PWV), which is a marker of aortic arterial stiffness (AS). AS is an important CV and prognostic marker. Therefore, in the third and last part of this work, 1 focus on how other nutritional factors could influence this parameter. The Matrix Gla protein (MGP), which needs vitamin K to be activated, protects against vascular calcification in its active form only. In this work, I demonstrate how its inactive form is not only associated to an increase in AS as measured by PWV, but also in RRL coirelating with alteration in rénal hemodynamic. On the contrary, caffeine intake could be protective, as it is associated with decreased PWV, and therefore AS. This could be a mechanistic explanation on the capacity of caffeine métabolites to lower blood pressure. In conclusion, within this thesis I am willing to show how kidney function, central and renal hemodynamic are interconnected and how some non-traditional and nutritional factors can explain some of the increased CV risk in certain populations such as CKD patients. -- Les patients atteints de maladies rénales chroniques décèdent fréquemment de maladies cardiovasculaires (’CV). Age. sexe, tabac, hypertension, diabète, dyslipidémie et anamnèse familiale positive sont considérés comme des facteurs de risque CV classiques. Toutefois, d’autres facteurs semblent influencer lerisque CV des patients atteints de maladies rénales. Certains facteurs nutritionnels notamment semblent jouer un rôle à la ibis sur la fonction des reins et sur l'atteinte vasculaire et pourraient être intéressants afin de limiter la progression de ces maladies. Une protéine synthétisée par le rein, l’uromodulin, semble être un marqueur de la masse rénale. Nous montrons ici en plus son lien avec la pression artérielle et le risque CV. à travers la modulation de l’absorption du sodium. Cette protéine pourrait être un marqueur de la sensibilité au sel. Nous nous sommes ensuite intéressés à l’effet du sel sur la fonction rénale. Nous démontrons dans ce travail, qu'une excrétion augmentée de sodium urinaire, correspondant à une prise plus importante de sel, accélère la perte de fonction liée à l’âge. L’hypothèse d'un effet direct du sodium sur les micro-vaisseaux est soutenue par la démonstration d’une augmentation de marqueurs de l’hémodynamique rénale avec la prise sodée, sans effet sur la rigidité artérielle systémique. Dans la dernière partie, nous regardons différents éléments nutritionnels qui pourraient avoir un impact sur la rigidité artérielle, qui est un marqueur important du risque et pronostic CV. La protéine Matrix Gla protein (MGP), sous sa forme active empêche les calcifications vasculaires. Hors son activation dépend de la vitamine K. Nous observons que la forme inactive est associée à une augmentation de la rigidité artérielle systémique et à l’hémodynamique rénale. Le café a été associé en prise chronique à la baisse de la pression artérielle, dont le mécanisme pourrait être un effet direct sur les vaisseaux. Pour soutenir cette hypothèse, nous établissons que certains métabolites de la cafféine sont associés à une diminution de la rigidité artérielle. En conclusion, dans cette thèse, je démontre comment la fonction rénale, l’atteinte vasculaire et l’hémodynamique rénale sont connectés et comment certains facteurs nutritionnels peuvent expliquer l’augmentation du risque cardio-vasculaire en relation avec l’atteinte rénale