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

A versatile clearing agent for multi-modal brain imaging

Extensive mapping of neuronal connections in the central nervous system requires high-throughput um-scale imaging of large volumes. In recent years, different approaches have been developed to overcome the limitations due to tissue light scattering. These methods are generally developed to improve the performance of a specific imaging modality, thus limiting comprehensive neuroanatomical exploration by multimodal optical techniques. Here, we introduce a versatile brain clearing agent (2,2'-thiodiethanol; TDE) suitable for various applications and imaging techniques. TDE is cost-efficient, water-soluble and low-viscous and, more importantly, it preserves fluorescence, is compatible with immunostaining and does not cause deformations at sub-cellular level. We demonstrate the effectiveness of this method in different applications: in fixed samples by imaging a whole mouse hippocampus with serial two-photon tomography; in combination with CLARITY by reconstructing an entire mouse brain with light sheet microscopy and in translational research by imaging immunostained human dysplastic brain tissue.Comment: in Scientific Reports 201

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

Reconstruction and simulation of neocortical microcircuitry

We present a first-draft digital reconstruction of the microcircuitry of somatosensory cortex of juvenile rat. The reconstruction uses cellular and synaptic organizing principles to algorithmically reconstruct detailed anatomy and physiology from sparse experimental data. An objective anatomical method defines a neocortical volume of 0.29 ± 0.01 mm3 containing ∼31,000 neurons, and patch-clamp studies identify 55 layer-specific morphological and 207 morpho-electrical neuron subtypes. When digitally reconstructed neurons are positioned in the volume and synapse formation is restricted to biological bouton densities and numbers of synapses per connection, their overlapping arbors form ∼8 million connections with ∼37 million synapses. Simulations reproduce an array of in vitro and in vivo experiments without parameter tuning. Additionally, we find a spectrum of network states with a sharp transition from synchronous to asynchronous activity, modulated by physiological mechanisms. The spectrum of network states, dynamically reconfigured around this transition, supports diverse information processing strategies

Large Volume Imaging of Rodent Brain Anatomy with Emphasis on Selective Plane Illumination Microscopy

Inside the human brain there are 86 Billion neurons exchanging electrical impulses to allow reaction, homoeostasis and intelligence. Their coarse organization has been described, leaving us with a fair understanding of macrocircuitry. The microcircuitry of the brain is also being explored with patch clamp recordings. But a more integrative view on mesoscale organization of the central nervous system is still lacking. Recent developments in microscopy methods have opened new windows to address this point. It is the goal of this thesis to analyze and compare anatomical features of the brain with current routine techniques as well as explore light sheet microscopy for large scale quantitative reconstructions of rodent brains. Integration efforts of the cortical column model of the Blue Brain project into more detailed cortical circuitry sparked the search of acute slice preparations suitable for long range electrophysiology. Serial section reconstruction of the rat S1 hindlimb anterograde projections was performed with special attention to the anatomical relationship between S1 hindlimb region and VPL nucleus of thalamus. It was found that a functional electrophysiological slice preparation between S1-HL and VPL is feasible. The subsequent experimental exploration proved the intact fiber path in acute slice preparations based on the morphometric measurements of the previous serial sectioning reconstruction. Another mesoscale trait investigated was the excitatory to inhibitory ratio of the juvenile rat cortex. The measured numbers for the cellular density are higher than previously published. Cellular density for S1-HL is 84535$\pm$4400 neurons/mm$^{3}$ high with an E-I ratio of 8.3. Like in other brains the cellular density is a continuously adapting function of the distance from pia and the current brain region. In the second part of this dissertation Selective Plane Illumination Microscopy(SPIM) and tissue clearing are evaluated as novel tools for whole mount rodent brain scanning, with emphasis on somata, fibers and vasculature as quantifiable brain features. Clearing methods are evaluated and a novel embedding medium for cleared tissues is presented: Thiodiethanol(TDE). Index matched brains with TDE show high degree of fluorescence conservation and transparency. Whole mount mouse and rat brains are imaged and reconstructed. The results show that whole mount microscopy is a potent tool that allows routine quantification of anatomic features on a whole brain level

Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline

Background Zinc deficiency is commonly encountered in chronic kidney disease (CKD). The aims of this study were to assess whether zinc deficiency was related to increased renal excretion of zinc and to the progression of CKD. Methods Plasma and 24-h urinary zinc levels, urinary electrolytes and uromodulin were measured in 108 CKD patients and 81 individuals without CKD. Serum creatinine values were collected for 3 years to calculate the yearly change in estimated glomerular filtration rate (eGFR). Multivariable regression analysis was performed to assess the association between baseline zinc levels and yearly change in eGFR. Results CKD patients had lower circulating zinc levels and higher 24-h urinary zinc excretion than non-CKD participants (612.4 ± 425.9 versus 479.2 ± 293.0 µg/day; P = 0.02). Fractional excretion (FE) of zinc was higher and it significantly increased at more advanced CKD stages. Zinc FE was correlated negatively with 24-h urinary uromodulin excretion (r=−0.29; P < 0.01). Lower baseline plasma zinc levels were associated with a faster yearly decline of renal function in age, gender, diabetes and hypertension adjusted models, but this relationship was no longer significant when baseline eGFR or proteinuria were included. Conclusions Zinc levels are lower in CKD, and not compensated by reduced renal zinc excretion. The inverse association between urinary zinc excretion and uromodulin possibly points to an impaired tubular activity, which could partly account for zinc imbalance in CKD. These data suggest that zinc status is associated with renal function decline, but further studies elucidating the underlying mechanisms and the potential role of zinc supplements in CKD are needed

Renal handling of zinc in chronic kidney disease patients and the role of circulating zinc levels in renal function decline

Background. Zinc deficiency is commonly encountered in chronic kidney disease (CKD). The aims of this study were to assess whether zinc deficiency was related to increased renal excretion of zinc and to the progression of CKD. Methods. Plasma and 24-h urinary zinc levels, urinary electrolytes and uromodulin were measured in 108 CKD patients and 81 individuals without CKD. Serum creatinine values were collected for 3 years to calculate the yearly change in estimated glomerular filtration rate (eGFR). Multivariable regression analysis was performed to assess the association between baseline zinc levels and yearly change in eGFR. Results. CKD patients had lower circulating zinc levels and higher 24-h urinary zinc excretion than non-CKD participants (612.4 +/- 425.9 versus 479.2 +/- 293.0 mu g/day; P = 0.02). Fractional excretion (FE) of zinc was higher and it significantly increased at more advanced CKD stages. Zinc FE was correlated negatively with 24-h urinary uromodulin excretion (r= -0.29; P &lt; 0.01). Lower baseline plasma zinc levels were associated with a faster yearly decline of renal function in age, gender, diabetes and hypertension adjusted models, but this relationship was no longer significant when baseline eGFR or proteinuria were included. Conclusions. Zinc levels are lower in CKD, and not compensated by reduced renal zinc excretion. The inverse association between urinary zinc excretion and uromodulin possibly points to an impaired tubular activity, which could partly account for zinc imbalance in CKD. These data suggest that zinc status is associated with renal function decline, but further studies elucidating the underlying mechanisms and the potential role of zinc supplements in CKD are needed