Background
Chronic kidney disease (CKD) is associated with increased risk of renal and cardiovascular events. It has been claimed that endogenous methylarginines, asymmetric dimethylarginine (ADMA) ...and symmetric dimethylarginine (SDMA), are contributing factors. However, earlier studies were partly contradictory and mainly focused on prevalent dialysis patients. Moreover, the potential contribution of degradation products, such as acetylated ADMA and SDMA (AcADMA and AcSDMA) and other methylarginines including L-N
G
-monomethylarginine (LNMMA) remains unknown. To better understand their potential pathophysiological contribution to renal and cardiovascular events, we aimed to provide a comprehensive analysis of methylarginines in a cohort of patients with non-dialysis CKD.
Methods
Blood samples of 528 patients with CKD KDIGO G2 to G4 were obtained from the
CARE FOR HOMe
study. Baseline plasma levels of ADMA, SDMA, AcADMA, AcSDMA, and LNMMA were measured by liquid chromatography—tandem mass spectrometry. All patients were followed annually for CKD progression and for incident atherosclerotic cardiovascular events.
Results
During 5.1 ± 2.1 years follow-up, 80 patients displayed CKD progression and 145 patients developed incident atherosclerotic cardiovascular events. In univariate Cox regression analyses, elevated plasma levels of all five metabolites were associated with both CKD progression and atherosclerotic cardiovascular disease. However, adjustment for confounders attenuated the prognostic implications of ADMA, LNMMA, AcADMA and AcSDMA. In contrast, patients in the highest tertile of plasma SDMA remained at highest risk for CKD progression and incident atherosclerotic cardiovascular events in fully adjusted Cox regression analyses.
Conclusion
Our results underline a potential pathophysiological role of SDMA in CKD progression and atherosclerotic cardiovascular disease among non-dialysis CKD patients. SDMA predicts CKD progression and future atherosclerotic cardiovascular events more consistently than other methylarginines. Future experimental and clinical studies should therefore focus upon SDMA rather than upon ADMA.
Trimethylamine N-oxide (TMAO) is a gut bacteria-mediated liver metabolite of dietary betaine, choline, and carnitine, which is excreted by glomerular filtration. We studied whether TMAO is excreted ...by cardiovascular disease (CVD) in patients with chronic kidney disease (CKD).
Among 478 patients with CKD stage G2 (n = 104), G3a (n = 163), G3b (n = 123), and G4 (n = 88), we studied the association between fasting plasma concentrations of TMAO, choline, or betaine at baseline and kidney function, prevalent CVD, and future renal outcomes during a mean follow-up of 5.1 years.
Decreased glomerular filtration rate was associated with higher plasma concentrations of TMAO, choline, and betaine. Baseline concentrations of TMAO were higher in participants with preexisting CVD compared to those without CVD (8.4 10.1 vs. 7.8 8.0 μmol/L; P = .047), but the difference was not significant after adjusting for confounders. During the follow-up, 147 participants experienced CVD or died, and 144 reached the predefined renal endpoint. In the adjusted regression analyses, TMAO or choline concentrations in the upper three quartiles (vs. the lowest quartile) were not associated with any of the study’s clinical endpoints. In contrast, the adjusted hazard ratio of plasma betaine in the highest quartile versus the lowest quartile was 2.14 (1.32, 3.47) for the CVD endpoint and 1.64 (1.00, 2.67) for the renal endpoint.
Elevated plasma TMAO concentrations were explained by impaired kidney function. Elevated plasma concentrations of betaine, but not those of TMAO or choline, constituted a risk factor for adverse outcomes. TMAO might not be an appropriate target to reduce CVD or renal outcomes in patients with preexisting CKD.
Many central nervous system regions at all stages of life contain neural stem cells (NSCs). We explored how these disparate NSC pools might emerge. A traceable clone of human NSCs was implanted ...intraventricularly to allow its integration into cerebral germinal zones of Old World monkey fetuses. The NSCs distributed into two subpopulations: One contributed to corticogenesis by migrating along radial glia to temporally appropriate layers of the cortical plate and differentiating into lamina-appropriate neurons or glia; the other remained undifferentiated and contributed to a secondary germinal zone (the subventricular zone) with occasional members interspersed throughout brain parenchyma. An early neurogenetic program allocates the progeny of NSCs either immediately for organogenesis or to undifferentiated pools for later use in the "postdevelopmental" brain.
Abstract Atherosclerosis has been characterized as an inflammatory process, in which monocytes and monocyte-derived macrophages are of paramount importance. Contrasting with their established role in ...atherosclerosis, monocytes have not unanimously been found to predict cardiovascular events in large epidemiological studies. However, in these studies human monocyte heterogeneity has been largely overlooked so far. Three human monocyte subsets can be distinguished: classical CD14++ CD16− , intermediate CD14++ CD16+ and nonclassical CD14+ CD16++ monocytes. Of note, correct enumeration of subset counts requires appropriate staining and gating strategies that encompass a pan-monocytic marker ( e.g. HLA-DR or CD86). In experimental studies on murine atherogenesis a monocyte subset-specific contribution to atherosclerosis has been established. However, major interspecies differences in atherogenesis itself, as well as in the immune system (including monocyte subset phenotype and distribution) preclude a direct extrapolation to human pathology. Experimental and pilot clinical studies point to a prominent involvement of intermediate CD14++ CD16+ monocytes in human atherosclerosis. Future clinical studies should analyze monocyte heterogeneity in cardiovascular disease. If a specific contribution of intermediate monocytes should be confirmed, immunomodulation of this monocyte subset could represent a future therapeutic target in atherosclerosis.
Introduction
Hydrophilic modification with polyvinylpyrrolidone (PVP) increases the biocompatibility profile of synthetic dialysis membranes. However, PVP may be eluted into the patient's blood, ...which has been discussed as a possible cause for adverse reactions rarely occurring with synthetic membranes. We investigated the content of PVP and its elution from the blood‐side surface from commercially available dialyzers, including the novel FX CorAL, with PVP‐enriched and α‐tocopherol‐stabilized membrane, and link the results to the level of platelet loss during dialysis as a maker of biocompatibility.
Methods
Six synthetic, PVP containing, dialyzers (FX CorAL, FX CorDiax Fresenius Medical Care; Polyflux, THERANOVA Baxter; ELISIO Nipro; xevonta B. Braun) were investigated in the present study. The content of PVP on blood‐side surface was determined with X‐ray photoelectron spectroscopy (XPS). The amount of elutable PVP was measured photometrically after 5 h recirculation. The level of platelet loss was evaluated in an ex vivo recirculation model with human blood.
Findings
Highest PVP content on the blood‐side surface was found for the polysulfone‐based FX CorAL (26.3%), while the polyethersulfone‐based THERANOVA (15.6%) had the lowest PVP content. Elution of PVP was highest for the autoclave steam‐sterilized THERANOVA (9.1 mg/1.6 m2 dialyzer) and Polyflux (9.0 mg/1.6 m2 dialyzer), while the lowest PVP elution was found for the INLINE steam sterilized FX CorAL and FX CorDiax (<0.5 mg/1.6 m2 dialyzer, for both). Highest platelet loss was found for xevonta (+164.4% compared to the reference) and the lowest for the FX CorAL (−225.2%) among the polysulfone‐based dialyzers; among the polyethersulfone‐based dialyzers, THERANOVA (+95.5%) had the highest and ELISIO (−52.1%) the lowest platelet loss.
Discussion
Polyvinylpyrrolidone content and elution differ between commercially available dialyzers and were found to be linked to the membrane material and sterilization method. The amount of non‐eluted PVP on the blood‐side surface may be an important determinant for the biocompatibility of dialyzers.
Background
Toxin removal capacity (i.e., performance) of a dialyzer is not constant but diminishes during treatment, as the adsorption of proteins to the membrane provides an additional barrier to ...uremic solutes. We investigated time‐resolving molecular weight retention changes among synthetic high‐flux dialyzers and compared the results with recent data from a randomized controlled trial.
Methods
In plasma recirculation experiments over 240 min, sieving coefficients (SC) for β2‐microglobulin, myoglobin, and albumin were determined for the FX CorAL (Fresenius Medical Care), ELISIO (Nipro), and xevonta (B. Braun). Molecular weight retention (MWR) curves were generated and the shifts over 120 min were characterized. Effective pore radius was determined, and the predicted albumin loss was compared with clinical data.
Results
SC decreased over time for all dialyzers (mean relative decrease across all dialyzers: β2‐microglobulin: 8.0% (120 min); myoglobin: 56.6% (240 min); albumin: 94.1% (240 min)). FX CorAL (7.3%, 52.6% and 91.1%) and ELISIO (7.7%, 51.0%, and 93.8%) showed a lower decrease than xevonta (9.0%, 66.2%, and 97.4%). For all dialyzers, MWR curves shifted toward lower molecular weight, with the lowest shift for FX CorAL (by 0.23 nm at SC50%, 120 min) and highest for xevonta (0.50 nm). FX CorAL had the highest slope over time and the smallest decrease in the effective pore radius (2 min: 2.31 nm, 120 min: 2.08 nm). Predicted albumin loss over 4 h was highest for xevonta (609.3 mg) and comparable between ELISIO (283.6 mg) and FX CorAL (313.3 mg).
Conclusions
Substantial differences in the temporal performance profile of dialyzers exist. The present approach allows the characterization of dialyzer permeability changes over time using standard, clinically relevant protein markers.
Background
Application of genetically modified bone marrow concentrates in articular cartilage lesions is a promising approach to enhance cartilage repair by stimulating the chondrogenic ...differentiation processes in sites of injury.
Method
In the present study, we examined the potential benefits of transferring the proliferative and pro-chondrogenic basic fibroblast growth factor (FGF-2) to human bone marrow aspirates in vitro using the clinically adapted recombinant adeno-associated virus (rAAV) vectors to monitor the biological and chondrogenic responses over time to the treatment compared with control (
lacZ
) gene application.
Results
Effective, significant FGF-2 gene transfer and expression via rAAV was established in the aspirates relative to the
lacZ
condition (from ~ 97 to 36 pg rhFGF-2/mg total proteins over an extended period of 21 days). Administration of the candidate FGF-2 vector led to prolonged increases in cell proliferation, matrix synthesis, and chondrogenesis but also to hypertrophic and terminal differentiation in the aspirates.
Conclusion
The present evaluation shows the advantages of rAAV-mediated FGF-2 gene transfer to conveniently modify bone marrow concentrates as a future approach to directly treat articular cartilage lesions, provided that expression of the growth factor is tightly regulated to prevent premature hypertrophy in vivo.
We present a proof-of-principle experiment demonstrating the use of atomic optical clocks as a frequency reference in Doppler-limited molecular spectroscopy. We report the determination of an ...unperturbed line position with a relative uncertainty of 2 × 10-11.
There are safety issues regarding plant sterol ester-enriched functional food. Oxidized plant sterols, also called oxyphytosterols, are supposed to contribute to plant sterol atherogenicity. This ...study aimed to analyze associations of plasma oxyphytosterol levels with cardiovascular events.
Plasma cholesterol was measured by gas chromatography-flame ionization detection. Plasma campesterol and sitosterol and their 7-oxygenated metabolites were analyzed by gas chromatography-mass selective detection.
In 376 patients admitted for elective coronary angiography, who were not on lipid-lowering drugs, 82 cardiovascular events occurred during a follow-up period of 4.2 ± 1.8 years. Patients with cardiovascular events had significantly higher 7α-hydroxycampesterol plasma levels (median, 0.46; interquartile range (IQR) 0.22–0.81 nmol/L vs. median, 0.25 IQR, 0.17–0.61 nmol/L; p = 0.003) and 7α-hydroxycampesterol-to-cholesterol ratios (median 0.08 IQR, 0.04–0.14 nmol/mmol vs. median, 0.05 IQR 0.03–0.11 nmol/mmol; p = 0.005) than controls without such events. Patients above the median were characterized by higher cumulative event rates in Kaplan-Meier-analysis (Logrank-test p = 0.084 and p = 0.025) for absolute and cholesterol corrected 7α-hydroxycampesterol, respectively. After adjustment for influencing factors and related lipids, the hazard ratios per one standard deviation of the log-transformed variables (HR) were 1.19 95% confidence interval (CI), 0.95–1.48, p = 0.132 for 7α-hydroxycampesterol and HR, 1.18 95% CI, 0.94–1.48, p = 0.154 for 7α-hydroxycampesterol-to-cholesterol ratio. None of the other investigated oxyphytosterols showed an association with cardiovascular events.
In patients not on lipid-lowering drugs, absolute plasma levels of 7α-hydroxycampesterol and their ratios to cholesterol are associated with cardiovascular events. Further research is required to elucidate the role of OPS in cardiovascular diseases.
Display omitted
•Plasma 7α-OH-Camp concentrations are associated with cardiovascular events.•None of the other investigated oxyphytosterols (OPS) show association with cardiovascular events.•Plant sterols (PS) and their respective OPS correlate significantly in plasma samples.
PDF
