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A catalog of genetic loci associated with kidney function from analyses of a million individuals
(2019)
Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Malnutrition is widespread in older people and represents a major geriatric syndrome with multifactorial etiology and severe consequences for health outcomes and quality of life. The aim of the present paper is to describe current approaches and evidence regarding malnutrition treatment and to highlight relevant knowledge gaps that need to be addressed. Recently published guidelines of the European Society for Clinical Nutrition and Metabolism (ESPEN) provide a summary of the available evidence and highlight the wide range of different measures that can be taken—from the identification and elimination of potential causes to enteral and parenteral nutrition—depending on the patient’s abilities and needs. However, more than half of the recommendations therein are based on expert consensus because of a lack of evidence, and only three are concern patient-centred outcomes. Future research should further clarify the etiology of malnutrition and identify the most relevant causes in order to prevent malnutrition. Based on limited and partly conflicting evidence and the limitations of existing studies, it remains unclear which interventions are most effective in which patient groups, and if specific situations, diseases or etiologies of malnutrition require specific approaches. Patient-relevant outcomes such as functionality and quality of life need more attention, and research methodology should be harmonised to allow for the comparability of studies.
Chemostat experiments are employed to study predator-prey and other trophic interactions, frequently using phytoplankton-zooplankton systems. These experiments often use population dynamics as fingerprints of ecological and evolutionary processes, assuming that the contributions of all major actors to these dynamics are known. However, bacteria are often neglected although they are frequently present. We argue that even without external carbon input bacteria may affect the experimental outcomes depending on experimental conditions and the physiological traits of bacteria, phytoplankton, and zooplankton. Using a static carbon flux model and a dynamic simulation model, we predict the minimum and maximum impact of bacteria on phytoplankton-zooplankton population dynamics. Under bacteria-suppressing conditions, we find that the effect of bacteria is indeed negligible and their omission justified. Under bacteria-favoring conditions, however, bacteria may strongly affect average biomasses of phytoplankton and zooplankton. The population dynamics may become highly complex, which may result in wrong interpretations when inferring processes (e.g., trait changes) from population dynamic patterns without considering bacteria. We provide suggestions to reduce the bacterial impact experimentally. Besides optimizing experimental conditions (e.g., the dilution rate) the appropriate choice of the zooplankton predator is decisive. Counterintuitively, bacteria have a larger impact if the predator is not bacterivorous as high bacterial biomasses and complex population dynamics arise via competition for nutrients with the phytoplankton. Only at least partial bacterivory minimizes the impact of bacteria. Our results help to improve the design of chemostat experiments and their interpretation, and advance the study of ecological and evolutionary processes in aquatic food webs.
High-pressure experiments were performed to investigate the effectiveness, rate and mechanism of carbonation of serpentinites by a carbon-saturated COH fluid at 1.5-2.5 GPa and 375-700 degrees C. This allows a better understanding of the fate and redistribution of slab-derived carbonic fluids when they react with the partially hydrated mantle within and above the subducting slab under pressure and temperature conditions corresponding to the forearc mantle. Interactions between carbon-saturated CO2-H2O-CH4 fluids and serpentinite were investigated using natural serpentinite cylinders with natural grain sizes and shapes in piston-cylinder experiments. The volatile composition of post-run fluids was quantified by gas chromatography. Solid phases were examined by Raman spectroscopy, electron microscopy and laser ablation inductively coupled plasma mass spectrometry. Textures, porosity and phase abundances of recovered rock cores were visualized and quantified by three-dimensional, high-resolution computed tomography. We find that carbonation of serpentinites is efficient at sequestering CO2 from the interacting fluid into newly formed magnesite. Time-series experiments demonstrate that carbonation is completed within similar to 96 h at 2 GPa and 600 degrees C. With decreasing CO2, aq antigorite is replaced first by magnesite + quartz followed by magnesite + talc + chlorite in distinct, metasomatic fronts. Above antigorite stability magnesite + enstatite + talc + chlorite occur additionally. The formation of fluid-permeable reaction zones enhances the reaction rate and efficiency of carbonation. Carbonation probably occurs via an interface-coupled replacement process, whereby interconnected porosity is present within reaction zones after the experiment. Consequently, carbonation of serpentinites is self-promoting and efficient even if fluid flow is channelized into veins. We conclude that significant amounts of carbonates may accumulate, over time, in the hydrated forearc mantle.