The dialyzer is the core element in the hemodialysis treatment of patients with end-stage kidney disease (ESKD). During hemodialysis treatment, the dialyzer replaces the function of the kidney by ...removing small and middle-molecular weight uremic toxins, while retaining essential proteins. Meanwhile, a dialyzer should have the best possible hemocompatibility profile as the perpetuated contact of blood with artificial surfaces triggers complement activation, coagulation and immune cell activation, and even low-level activation repeated chronically over years may lead to undesired effects. During hemodialysis, the adsorption of plasma proteins to the dialyzer membrane leads to a formation of a secondary membrane, which can compromise both the uremic toxin removal and hemocompatibility of the dialyzer. Hydrophilic modifications of novel dialysis membranes have been shown to reduce protein adsorption, leading to better hemocompatibility profile and performance stability during dialysis treatments. This review article focuses on the importance of performance and hemocompatibility of dialysis membranes for the treatment of dialysis patients and summarizes recent studies on the impact of protein adsorption and hydrophilic modifications of membranes on these two core elements of a dialyzer.
Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) ...is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored.
Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths.
PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 1.8-4.1 years and 10.0 7.3-10.6 years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort CARE FOR HOMe (p = 0.622); LURIC (p = 0.729). Sensitivity analyses according to statin intake yielded similar results.
In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which ...substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
The quality of Very Long Baseline Interferometry (VLBI) radio observations predominantly relies on precise and ultra-stable time and frequency (T&F) standards, usually hydrogen masers (HM), ...maintained locally at each VLBI station. Here, we present an operational solution in which the VLBI observations are routinely carried out without use of a local HM, but using remote synchronization via a stabilized, long-distance fibre-optic link. The T&F reference signals, traceable to international atomic timescale (TAI), are delivered to the VLBI station from a dedicated timekeeping laboratory. Moreover, we describe a proof-of-concept experiment where the VLBI station is synchronized to a remote strontium optical lattice clock during the observation.
Across the spectrum of clinical medicine, the field of epigenetics has gained substantial scientific interest in recent years. Epigenetics refers to modifications in gene expression which are not ...explained by changes in DNA sequence. Classical components of epigenetic regulation comprise DNA methylation, histone modifications and RNA interference. In chronic kidney disease (CKD), several features of uraemia, such as hyperhomocysteinemia and inflammation, may contribute to changes in epigenetic gene regulation. It has been suggested that these changes may affect genes related to cardiovascular disease. Thereby, a uraemia-associated disturbance in epigenetic regulation may contribute to the substantial increase in cardiovascular morbidity in CKD patients. The present review aims to summarize current knowledge of epigenetic dysregulation in cardiovascular disease from a nephrological perspective, with a special focus on DNA methylation. We first describe the impact of altered epigenetic regulation in non-CKD-associated arteriosclerosis, and next characterize uraemic features which may affect epigenetic gene regulation in the context of cardiovascular disease. Finally, we conclude that substantial additional work is needed before epigenetic regulatory mechanisms may become therapeutic targets in CKD-associated cardiovascular disease.
We present a comprehensive study of the frequency shifts associated with the lattice potential in a Sr lattice clock by comparing two such clocks with a frequency stability reaching 5×10(-17) after a ...1 h integration time. We put the first experimental upper bound on the multipolar M1 and E2 interactions, significantly smaller than the recently predicted theoretical upper limit, and give a 30-fold improved upper limit on the effect of hyperpolarizability. Finally, we report on the first observation of the vector and tensor shifts in a Sr lattice clock. Combining these measurements, we show that all known lattice related perturbations will not affect the clock accuracy down to the 10(-17) level, even for lattices as deep as 150 recoil energies.
Abstract Background Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage ...kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. Methods This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was β2-microglobulin removal rate (β2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. Results 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest β2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. Conclusions The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. Trial registration eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).
Despite the significant medical and technical improvements in the field of dialytic renal replacement modalities, morbidity and mortality are excessively high among patients with end-stage kidney ...disease, and most interventional studies yielded disappointing results. Hemodiafiltration, a dialysis method that was implemented in clinics many years ago and that combines the two main principles of hemodialysis and hemofiltration-diffusion and convection-has had a positive impact on mortality rates, especially when delivered in a high-volume mode as a surrogate for a high convective dose. The achievement of high substitution volumes during dialysis treatments does not only depend on patient characteristics but also on the dialyzer (membrane) and the adequately equipped hemodiafiltration machine. The present review article summarizes the technical aspects of online hemodiafiltration and discusses present and ongoing clinical studies with regards to hard clinical and patient-reported outcomes.
While efficient removal of uremic toxins and accumulated water is pivotal for the well-being of dialysis patients, protein adsorption to the dialyzer membrane reduces the performance of a dialyzer. ...Hydrophilic membrane modification with polyvinylpyrrolidone (PVP) has been shown to reduce protein adsorption and to stabilize membrane permeability. In this study we compared middle molecule clearance and filtration performance of nine polysulfone-, polyethersulfone-, and cellulose-based dialyzers over time. Protein adsorption was simulated in recirculation experiments, while β2-microglobulin clearance as well as transmembrane pressure (TMP) and filtrate flow were determined over time. The results of this study showed that β2-microglobulin clearance (-7.2 mL/min/m
) and filtrate flow (-54.4 mL/min) decreased strongly during the first 30 min and slowly afterwards (-0.7 mL/min/m
and -6.8 mL/min, respectively, for the next 30 min); the TMP increase (+37.2 mmHg and +8.6 mmHg, respectively) showed comparable kinetics. Across all tested dialyzers, the dialyzer with a hydrophilic modified membrane (FX CorAL) had the highest β2-microglobulin clearance after protein fouling and the most stable filtration characteristics. In conclusion, hydrophilic membrane modification with PVP stabilizes the removal capacity of middle molecules and filtration performance over time. Such dialyzers may have benefits during hemodiafiltration treatments which aim to achieve high exchange volumes.
Vascular calcification is a major contributor to the high cardiac burden among hemodialysis patients. A novel in vitro T50-test, which determines calcification propensity of human serum, may identify ...patients at high risk for cardiovascular (CV) disease and mortality. We evaluated whether T50 predicts mortality and hospitalizations among an unselected cohort of hemodialysis patients.
This prospective clinical study included 776 incident and prevalent hemodialysis patients from 8 dialysis centers in Spain. T50 and fetuin-A were determined at Calciscon AG, all other clinical data were retrieved from the European Clinical Database. After their baseline T50 measurement, patients were followed for two years for the occurrence of all-cause mortality, CV-related mortality, all-cause and CV-related hospitalizations. Outcome assessment was performed with proportional subdistribution hazards regression modelling.
Patients who died during follow-up had a significantly lower T50 at baseline as compared to those who survived (269.6 vs. 287.7 min, p = 0.001). A cross-validated model (mean c statistic: 0.5767) identified T50 as a linear predictor of all-cause-mortality (subdistribution hazard ratio (per min): 0.9957, 95% CI 0.9933;0.9981). T50 remained significant after inclusion of known predictors. There was no evidence for prediction of CV-related outcomes, but for all-cause hospitalizations (mean c statistic: 0.5284).
T50 was identified as an independent predictor of all-cause mortality among an unselected cohort of hemodialysis patients. However, the additional predictive value of T50 added to known mortality predictors was limited. Future studies are needed to assess the predictive value of T50 for CV-related events in unselected hemodialysis patients.
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