Abstract Background and Aims Chronic kidney disease (CKD) is one of the most common diseases affecting 8-16% of the world population. Beside cardiovascular complications, infections including sepsis ...are the second most common cause of death in patients with acute kidney injury (AKI) and CKD. However, the underlying pathomechanisms that contribute to the secondary immunodeficiency related to kidney disease 1 are not well understood. Recent evidence suggests that CKD-related hyperuricemia characterised by elevated serum uric acid (UA) levels suppresses immune cell functions during sterile inflammation 2. Whether this is also the case during host defense is subject of our current investigation. In this study, we hypothesized that soluble UA inhibits neutrophil effector functions and therefore contributes to the increased infection risk in patients with kidney disease. Method Blood neutrophils were isolated from healthy individuals as well as from patients with kidney diseases, and incubated ex vivo in the presence or absence of 10 mg/dl soluble UA prior to stimulation with bacterial peptides including LPS. Immune cell functions including cytoskeletal changes, immune cell activation, maturation, endo- and phagocytosis (pHrodo Dextran particles, IgG-FITC beads, pHrodo E. coli bioparticles), ROS production, and neutrophil extracellular trap (NET) formation were analysed and quantified using flow cytometry, fluorescence and colorimetric assays, and fluorescence microscopy. In addition, to verify our results we stimulated neutrophils from healthy individuals with sera from hyperuricemic CKD patients. Results Our results show for the first time that soluble UA significantly inhibits the ability of neutrophils to endocytose small particles and phagocytose beads in neutrophils from healthy individuals comparable to the inhibitory effect of Cytochalasin D, an inhibitor of endo- and phagocytosis. Interestingly, unlike neutrophils from AKI patients, neutrophils from CKD patients were significantly less able to phagocytose beads compared to healthy controls with and without stimulation. To mimic the uptake of pathogens more physiologically, pHrodo E. coli bioparticles were used. We found that soluble UA inhibited the phagocytosis of such bioparticles in neutrophils. In addition, our investigation into the formation of ROS showed that soluble UA inhibited specifically nitric oxide, peroxynitrite, hydroxyl radicals and hydrogen peroxide, but to a lower extent the formation of superoxides in neutrophils from healthy individuals, similar to the effectiveness of the radical scavenger N-acetylcysteine. These data were comparable with our cohort study of neutrophils from CKD patients. To examine the mechanism of reduced ROS production, we inhibited NADPH oxidase (DPI) and MPO (4-ABAH) in neutrophils and found that soluble UA has similar inhibitory effects on ROS production like DPI whereas 4-ABAH was more potent. This indicated that soluble UA modulates NADPH oxidase and ROS production, which subsequently resulted in reduced NET formation in neutrophils. Conclusion Our data identify soluble UA as potential immune regulator of the secondary immunodeficiency in patients with kidney disease by inhibiting the endo- and phagocytosis of particles, NADPH-mediated ROS production and NET formation in neutrophils, processes that are important to kill pathogens and fight an infection. Thus, specifically targeting UA with urate-lowering therapy might overcome the suppressed host defence against infection in patients with kidney disease.
ABSTRACT
Asymptomatic hyperuricaemia (HU) is considered a pathogenic factor in multiple disease contexts, but a causative role is only proven for the crystalline form of uric acid in gouty arthritis ...and urate nephropathy. Epidemiological studies document a robust association of HU with hypertension, cardiovascular disease (CVD) and CKD progression, but CKD-related impaired uric acid (UA) clearance and the use of diuretics that further impair UA clearance likely accounts for these associations. Interpreting the available trial evidence is further complicated by referring to xanthine oxidase inhibitors as urate-lowering treatment, although these drugs inhibit other substrates, so attributing their effects only to HU is problematic. In this review we provide new mechanistic insights into the biological effects of soluble and crystalline UA and discuss clinical evidence on the role of asymptomatic HU in CKD, CVD and sterile inflammation. We identify research areas with gaps in experimental and clinical evidence, specifically on infectious complications that represent the second common cause of death in CKD patients, referred to as secondary immunodeficiency related to kidney disease. In addition, we address potential therapeutic approaches on how and when to treat asymptomatic HU in patients with kidney disease and where further interventional studies are required.
Lay Summary
Asymptomatic hyperuricaemia (HU) has a documented causative role in gouty arthritis, kidney stones and urate nephropathy, disorders that are attributed to uric acid (UA) in its crystalline form and are characterized by the pro-inflammatory effects of UA crystals. In contrast, soluble UA/HU has been associated with hypertension, cardiovascular disease (CVD) and the progression of chronic kidney disease (CKD), but a causative link has not been secured. Recent experimental data indicate that soluble UA/asymptomatic HU acts as a suppressor of innate immunity. Thus soluble and crystalline UA seem to have opposite effects. In this review we highlight new mechanistic insights on the effects of soluble versus crystalline UA and provide clinical evidence on the role of asymptomatic HU in CKD, CVD and the secondary immunodeficiency in host defence and sterile inflammation. Additionally, we provide potential therapeutic approaches on when and how to treat asymptomatic HU in patients with kidney disease.
Graphical Abstract
Graphical Abstract
As a wide band gap semiconductor, gallium nitride (GaN) has high breakdown voltage, excellent structural stability and mechanical properties, giving it unique advantages in applications such as high ...frequency, high power, and high temperature. As a result, it has broad application prospects in optoelectronics and microelectronics. However, the lack of high‐quality, large‐size GaN crystal substrates severely limit the improvement of electronic device performance. To solve this problem, liquid phase growth of GaN has attracted much attention because it can produce higher quality GaN crystals compared to traditional vapor phase growth methods. This review introduces two main methods of liquid phase growth of GaN: the flux method and ammonothermal method, as well as their advantages and challenges. It reviews the research history and recent advances of these two methods, including the effects of different solvents and mineralizers on the growth quality and performance of GaN crystals, as well as various technical improvements. This review aims to outline the principles, characteristics, and development trends of liquid phase growth of GaN, to provide more inspiration for future research on liquid phase growth, and to achieve further breakthroughs in its development and commercial application.
The flux and ammonothermal methods are capable of the growth of large size, high quality GaN crystals, which are the main methods of liquid phase growth. The research progress of these two growth methods in terms of chemical additives and growth process is summarised, and their application prospects in industrial production are discussed.
To compare the safety and efficacy of total tubeless percutaneous nephrolithotomy (PCNL) with standard PCNL for the treatment of upper urinary calculi. PubMed, EMBASE, Cochrane Library and ...ScienceDirect were searched for collecting related literature on the two procedures. All compared studies, including randomized controlled trials (RCT), cohort studies (CS) and case-control studies (CCS), were included. Totally, 14 studies were included. Pooled data demonstrated that patients who underwent total tubeless PCNL were associated with significantly shorter operation time weighted mean difference (WMD): −3.41, P = 0.004, shorter hospital stay (WMD: −1.54, P < 0.00001). It seemed that significantly less postoperative analgesic requirement could be found in the total tubeless PCNL group according to subgroup analysis. However, no significant differences could be found between the two groups in stone-free rate risk ratio (RR): 1.03, P = 0.26, hemoglobin drop (WMD: −0.03, P = 0.85), and rates of postoperative fever (RR: 0.53, P = 0.11) and transfusion (RR: 0.79, P = 0.41). Sensitivity analysis after excluding CCS revealed results similar to previous findings. Total tubeless PCNL would be superior to standard PCNL in reducing operation time, hospital stay and postoperative analgesic requirement without significantly more adverse events.
Autosomal-recessive dopa-responsive dystonia (DRD) is a rare clinical disorder presenting as bradykinesia, dystonia, tremor and even severe encephalopathy, and caused by tyrosine hydroxylase ...deficiency (THD). We report a case of compound heterozygous mutations in the TH gene in a Chinese family with autosomal-recessive DRD herein.
A 16-month-old Chinese boy presented with symptoms of movement disorder and growth retardation in his infant period.
The genetic test revealed compound heterozygous mutations in the TH gene at c.457C>T and c.698G>A, which are pathogenic of DRD.
The patient was administrated low-dose levodopa.
The treatment resulted in the substantial improvement of dystonia. His long-term neurological outcome need follow-up for years.
Gene mutation analysis is helpful and necessary to diagnose DRD and has important guiding significance for the subsequent treatment.
Manufacturing defects in ceramic matrix composites (CMCs), such as voids, microcracks, etc., significantly affect the damage events and strength of the materials. This study aims to reveal the effect ...of void defects on the failure behavior and tensile strength of a plain-woven C/SiC composite. The mesoscopic architectures of the C/SiC composites are tested by micro-computed tomography. Based on the μ-CT images of the material, finite element models (IB-FEM) of the C/SiC composite are established with different void volume fractions and different void geometry. The tensile strength and fracture features of the C/SiC composites are calculated by using the IB-FEM. The effects of void volume fraction and geometry on failure behaviors and tensile strength of the C/SiC composites are investigated and discussed. This study is of great significance for further understanding the influence of defects on the mechanical behavior of CMCs.
Familial chylomicronemia syndrome (FCS) is a rare genetic disease. FCS usually manifests by the age of 10 years, and 25% of cases of FCS occur during infancy. Here we present a case of FCS in a male ...infant and summarize our experiences on the diagnosis and therapy of this case.
A male infant aged 1 month and 8 days had recurrent hematochezia and hyperchylomicronemia.
FCS based on symptoms and genetic test.
Plasma exchange therapy.
His development was normal with a good spirit and satisfactory weight gain, and no hematochezia occurred again.
Genetic test is important for accurate diagnosis of FCS, and we identified a new mutation of lipoprotein lipase gene c.88C>A which conformed to autosomal recessive inheritance. Plasma exchange therapy can be applied to infants with FCS with low risk and good outcomes.
Owing to its wide band gap, extreme mechanical hardness and high thermal conductivity, GaN has found widespread applications in optoelectronic devices and high-power/-frequency devices. However, the ...growth of high-quality and large-size GaN crystal substrates is still a great challenge, which hinders the development of power and radio frequency (RF) devices. The Na-flux method can emerge as an effective strategy to address these challenges. Nevertheless, the growth quality of GaN crystals is influenced by several factors during the growth process. This study focused on investigating the growth rate and quality of GaN in relation to the growth temperature and pressure. It also explains the difference in the solubility between N 3− and GaN as a function of temperature in liquid phase melts. The intricacy of the Na-flux method and the opacity of the growth process present significant obstacles to the growth of GaN crystals. In order to accurately determine and optimise the growth conditions, the temperature distribution and material transport during the growth process are predicted by simulation. A series of validation experiments were conducted to investigate the influence of temperature and pressure on GaN crystallisation. Under optimised growth conditions, high-quality GaN crystals with a full width at half maximum of 433 arcsec (002) were obtained. This work provides an effective strategy for the liquid-phase growth of high-quality GaN crystals, facilitating the development of high-performance blue-green lasers, RF and power devices.
With the energy crisis and environmental pollution, the development of sustainable new energy has become an urgent priority. These considerations make society aware that green energy technologies are ...critical to economic development. Electrochemical energy storage technology is a green energy technology based on the ability to exhibit high energy density (battery) or high power density (supercapacitor). There is a growing demand for high-energy and high-power-density electrochemical energy storage devices for current and future applications. However, the performance of electrochemical energy storage devices is limited by the activity of electrode materials. It is difficult to meet the demands of rapid economic development for energy equipment with high energy density, high power density and long life. The energy density of supercapacitors can be significantly improved by preparing novel active electrode materials. Research has found that new semiconductor materials have the potential to improve the cycle life, energy and power density of supercapacitors. To date, a variety of novel semiconductor electrode materials have been fabricated and studied for supercapacitors. This review summarizes the main advantages of several new semiconductor materials as electrode materials. In addition, the latest and representative progress in the development of electrode materials for supercapacitors is presented. Finally, current challenges are discussed and key perspectives for future research in this field are outlined.
This manuscript systematically reviews the research progress of novel semiconductor materials in the preparation and application of SCs.
PDF
