Muscle ultrasound to diagnose sarcopenia in chronic kidney disease: a systematic review and bayesian bivariate meta-analysis.

OBJECTIVE: The aim of this systematic review was to assess the diagnostic test accuracy of muscle ultrasound for sarcopenia among chronic kidney disease (CKD) populations. BACKGROUND: Sarcopenia has become a worldwide health issue, especially for CKD patients. Conventional techniques of muscle mass assessment often prove limited, thus prompts increasing interest in ultrasound suitability. METHODS: We searched the Cochrane Library, PubMed and Embase for literature published up to June 2023. Ultrasound diagnosis of sarcopenia in CKD patients was included. Two independent investigators used the Quality Assessment Tool for Diagnosis Accuracy Studies (QUADAS-2) to assess the quality. We extracted valuable information from eligible studies. Using a Bayesian bivariate model, we pooled sensitivity and specificity values and summary receiver operating characteristic (SROC) curves. RESULTS: Five articles, involving 428 participants at various stages of CKD were included. Three studies diagnosed by the cross-sectional area (CSA) of the rectus femoris, while two others by muscle thickness (MT) and shear wave elastography (SWE) from the same muscle, separately. Overall, CSA or SWE had a pooled sensitivity of 0.95 (95% CrI, 0.80, 1.00), and the specificity was 0.73 (95% CrI, 0.55, 0.88) for diagnosing sarcopenia in CKD patients. CONCLUSIONS: Ultrasound measurements of CSA and SWE were more sensitive for diagnosing sarcopenia in the CKD population than in the general population. Ultrasound assessment from a single peripheral skeletal muscle site may serve as a rapid screening tool for identifying sarcopenic individuals within the CKD population, if a specific cut-off value could be determined.

The fronto-central N2 but not parietal P3 reflects response inhibition in the count/no-count task.

This study aimed to investigate whether the N2 or P3 component in the count/no-count task reflects response inhibition. The participants were asked to count/withhold counting the number of O/X letters in the count/no-count task, and to calculate the sum of all digits (i.e., 1/0) in the digital accumulation task. Therefore, four conditions were obtained in this study: count, no-count, Add 1, and Add 0. In the count and Add 1 conditions, the counting/calculation number need to be updated. In both no-count and Add 0 conditions, the memory of counting/calculation number need not to be updated; a No-go (withhold) instruction was given in the no-count condition, but a Go instruction was given in the Add 0 condition. Results showed that an enhanced fronto-central N2 was evoked in the no-count than in the Add 0 condition, indicating that a stronger response conflict or stronger inhibition might be triggered in the No-count condition. The frontocentral P3 showed no differences between no-count and Add 0 conditions, however, an enhanced centro-parietal P3 component was observed for the count relative to the no-count condition and for the Add 1 relative to the Add 0 condition, indicating that a greater amount of attentional resources might be consumed during memory updating process. Taken together, in the count/no-count task, the fronto-central N2 might reflect response inhibition or conflict and the parietal P3 might reflect attentional resource allocation but not response inhibition.

Response inhibition and memory updating in the count/nocount task: an ERP study.

The present study aimed to separate the neural activities between response inhibition and memory updating processes in the Count/Nocount task. Memory load was manipulated to investigate the memory updating process. Within each trial, participants were asked to count/withhold counting the number of O/X letters in the Count/Nocount task. The participants were asked to silently add 1 if a Count letter was presented in the low load condition, and add 2 in the high load condition. Data from 28 healthy participants showed that: (1) in both high load and low load conditions, the latencies of P2 and N2 components were shorter for the Nocount than Count trials, indicating faster attentional orienting and conflict monitoring processes for the Nocount stimuli (i.e., inhibition processes triggered by the Nocount stimuli against those response execution processes triggered by Count stimuli); (2) more positive frontal P3 amplitudes were evoked for the Nocount relative to the Count stimuli, indicating a more intensive response inhibition process for the Nocount trials; (3) a more positive parietal P3 component was evoked for the low load relative to high load condition, indicating a more intensive working memory updating process for the high load condition. This load effect was absent for the frontal P3 component, suggesting that the frontal P3 might not be associated with the memory updating process. In sum, both the cognitive inhibition process (reflected by the frontal P3 component) and working memory updating process (reflected by the parietal P3 component) appear to be involved in the Count/Nocount task.

Visceral Fat Area Is a Better Predictor Than Coronary Artery Calcification Score for Cardiovascular Outcomes and All-Cause Death in Patients on Hemodialysis.

OBJECTIVES: The aim of this study is to compare the prognostic effects of visceral fat area (VFA) with coronary artery calcification score (CACs) in patients on maintenance hemodialysis. DESIGN AND METHODS: In the prospective study with no intervention, clinical characteristics and serum biochemical indexes at baseline for each patient were collected through the electronic medical records. Body composition assessment using bioelectrical impedance analysis, computed tomography examination with the Agatston scoring method, and echocardiographic measurements were performed at enrollment. Primary endpoints included cardiovascular events (CVEs), cardiovascular death (CVD), and all-cause death. RESULTS: A total of 97 Chinese patients aged 48 (35-62) years were enrolled from our Hemodialysis Center, of which 61.9% were male and 20.6% had diabetes. The median of VFA and CACs at baseline was 64.5 (43.5-88.7) cm2 and 0.9 (0-467.6), respectively. CVEs occurred in 20 (20.6%) patients during a median follow-up of 26.4 (13-27.7) months. The cardiovascular and all-cause mortality was 8.2% (8 patients) and 11.3% (11 patients), respectively. VFA was associated with CVEs (hazard ratio [HR] = 9.21 for VFA ≥71.3 cm2 vs. VFA <71.3 cm2, P = .017), CVD (HR = 1.11 for 1 cm2 increase, P = .035), and all-cause mortality (HR = 1.08 for 1 cm2 increase, P = .011). Also, VFA was significantly correlated with cardiac structure parameters and the development of left ventricular hypertrophy (odds ratio = 1.02 for 1 cm2 increase, P = .03). Yet, CACs were not correlated with CVEs, CVD, or all-cause mortality. CONCLUSIONS: Increased VFA can be used as an independent predictor for CVEs, CVD, and all-cause mortality. The effect VFA exerts on cardiac reconstruction might be the underlying mechanism. Further studies are warranted for the management of VFA in the hemodialysis population.

Association between Serum Soluble α-Klotho and Urinary Albumin Excretion in Middle-Aged and Older US Adults: NHANES 2007-2016.

(1) Background: Preclinical and clinical studies on the anti-aging effect of α-Klotho are emerging. Urinary albumin excretion (UAE) is a well-known biomarker of kidney injury and generalized damage in the cardiovascular system. However, the potential relationship between α-Klotho and UAE is limited and controversial. This study aimed to quantify this relationship in the general middle-aged and elderly population from the National Health and Nutrition Survey (NHANES) 2007-2016. (2) Methods: Serum α-Klotho was measured by enzyme-linked immunosorbent assay. UAE was assessed by the albumin-to-creatinine ratio (ACR). After adjusting for several confounding variables, the relationship between α-Klotho and ACR was analyzed by weighted multivariable logistic regression, subgroup analysis, and interaction tests. A generalized additive model (GAM) with smooth functions using the two-piecewise linear regression model was used to examine the potential nonlinear relationship between α-Klotho and ACR. (3) Results: Among 13,584 participants aged 40-79 years, we observed an independent and significant negative correlation between α-Klotho and ACR (ß = -12.22; 95% CI, -23.91, -0.53, p = 0.0448) by multivariable logistic regression analysis, especially in those with age ≥ 60 years, pulse pressure (PP) ≥ 60 mmHg, hypertension or diabetes. We further discovered the nonlinear relationship between α-Klotho and ACR by GAM, revealing the first negative and then positive correlations with an inflection point of 9.91 pg/mL between α-Klotho and ACR. (4) Conclusions: A dose-response relationship between α-Klotho and ACR was demonstrated, and the negative correlation therein indicated that α-Klotho has potential as a serum marker and prophylactic or therapeutic agent despite its metabolic and effective mechanisms needing to be further explored.

NOX4 is a potential therapeutic target in septic acute kidney injury by inhibiting mitochondrial dysfunction and inflammation.

Rationale: Sepsis is a severe clinical syndrome featured through organ dysfunction due to infection, while the accompanying acute kidney injury (AKI) is linked to significant incidence of morbidity as well as mortality. Recently, emerging evidence has revealed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) is implicated in various renal diseases, while its role and modulation in septic acute kidney injury (S-AKI) remains largely unknown. Methods: In vivo, S-AKI in wild-type and renal tubular epithelial cell (RTEC)-specific NOX4 knockout mice was induced by lipopolysaccharides (LPS) injection or cecal ligation and puncture (CLP). In vitro, TCMK-1 (mouse kidney tubular epithelium cell line) cells were treated with LPS. Serum and supernatant biochemical, mitochondrial dysfunctional, inflammatory and apoptotic parameters were measured and compared across groups. The activation of reactive oxygen species (ROS) and NF-κB signaling was also assessed. Results: NOX4 was predominantly upregulated in RTECs of S-AKI mouse model induced by LPS/CLP and cultured TCMK-1 cells exposed to LPS. RTEC-specific deletion of NOX4 or pharmacological inhibition of NOX4 by GKT137831 both alleviated LPS/CLP-injured renal function and pathology in mice. Furthermore, NOX4 inhibition alleviated mitochondrial dysfunction supported by ultrastructural damage, reduction of ATP production and mitochondrial dynamics imbalance, together with inflammation and apoptosis in kidney injured by LPS/CLP and TCMK-1 cells injured by LPS, while NOX4 overexpression aggravated the above-mentioned indices in TCMK-1 cells with LPS stimulation. Mechanism-wise, the raised NOX4 in RTECs may induce ROS and NF-κB signaling activation in S-AKI. Conclusions: Collectively, genetic or pharmacological inhibition of NOX4 protects from S-AKI by reducing generation of ROS and activation of NF-κB signal, which suppress mitochondrial dysfunction, inflammation together with apoptosis. NOX4 may act as a novel target for the S-AKI therapy.

Vascular Calcification Exacerbates Abnormal Blood Pressure Variability in Chronic Kidney Disease: A "Two-Step" Study in Rats.

INTRODUCTION: Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) with poor cardiovascular prognosis. The aim of this study was to explore the impact of VC on blood pressure variability (BPV) in animal models of CKD. METHODS: Two optimal modelling methods, adenine high-phosphorus (HP) diet + calcitriol and 5/6 nephrectomy (Nx) + HP diet + calcitriol, for CKD-VC were chosen from the first-step experiment for the next step. A total of 36 male Wistar rats were randomly assigned to the standard-chow, sham-operated, adenine, 5/6Nx, adenine-VC, and 5/6Nx-VC groups. Continuous blood pressure (BP) measurement using the BP-2000 animal noninvasive BP analyser was started at the 9th week for the standard-chow, adenine, and adenine-VC groups and at the 7th week for the sham-operated, 5/6Nx, and 5/6Nx-VC groups. BPV metrics (BPVs), including the difference between maximum and minimum values, standard deviation, coefficient of variation, average real variability, and residuals derived from the generalized linear model of BP, were calculated. RESULTS: The first experiment showed that the use of calcitriol accelerated the progression of VC in CKD rats (the modelling period was shortened from 16 weeks to 4-8 weeks) and confirmed the occurrence of VC at weeks 8 and 6 in the adenine-VC and 5/6Nx-VC groups, respectively. In the second experiment, 13 of 20 hour-to-hour BPVs increased significantly with the development of CKD and VC. BPV differences among the standard-chow, adenine, and adenine-VC groups were mainly due to the differences between the standard-chow and adenine-VC groups (7 of 10 BPVs were significantly different), followed by the differences between the standard-chow and adenine groups (3 of 10). BPV differences among the sham-operated, 5/6Nx, and 5/6Nx-VC groups were caused by the differences between the 5/6Nx-VC and 5/6Nx groups (4 of 10) or the 5/6Nx-VC and sham-operated groups (3 of 10). CONCLUSION: An increased BPV is observed in CKD rats, and VC further aggravates the abnormality of BPVs independent of CKD.

Effect of extracorporeal hemoadsorption in critically ill patients with COVID-19: A narrative review.

COVID-19 has been affecting the world unprecedentedly and will remain widely prevalent due to its elusive pathophysiological mechanism and the continuous emergence of new variants. Critically ill patients with COVID-19 are commonly associated with cytokine storm, multiple organ dysfunction, and high mortality. To date, growing evidence has shown that extracorporeal hemoadsorption can exert its adjuvant effect to standard of care by regulating immune homeostasis, reducing viremia, and decreasing endotoxin activity in critically ill COVID-19 cases. However, the selection of various hemofilters, timing of initiation and termination of hemoadsorption therapy, anticoagulation management of extracorporeal circuits, identification of target subgroups, and ultimate survival benefit remain controversial. The purpose of this narrative review is to comprehensively summarize the rationale for the use of hemoadsorption in critically ill patients with COVID-19 and to gather the latest clinical evidence in this field.

Effects of Expanded Hemodialysis with Medium Cut-Off Membranes on Maintenance Hemodialysis Patients: A Review.

Kidney failure is associated with high morbidity and mortality. Hemodialysis, the most prevalent modality of renal replacement therapy, uses the principle of semipermeable membranes to remove solutes and water in the plasma of patients with kidney failure. With the evolution of hemodialysis technology over the last half century, the clearance of small water-soluble molecules in such patients is adequate. However, middle molecules uremic toxins are still retained in the plasma and cause cardiovascular events, anemia, and malnutrition, which significantly contribute to poor quality of life and high mortality in maintenance hemodialysis patients. A new class of membrane, defined as a medium cut-off (MCO) membrane, has emerged in recent years. Expanded hemodialysis with MCO membranes is now recognized as the artificial kidney model closest to natural kidney physiology. This review summarizes the unique morphological characteristics and internal filtration-backfiltration mechanism of MCO membranes, and describes their effects on removing uremic toxins, alleviating inflammation and cardiovascular risk, and improving quality of life in maintenance hemodialysis patients.

The association between weight-adjusted-waist index and abdominal aortic calcification in adults aged ≥ 40 years: results from NHANES 2013-2014.

The negative effects of obesity on the cardiovascular health have drawn much attention. Weight-adjusted-waist index (WWI) has been proved to reflect weight-independent centripetal obesity. However, the association between WWI and abdominal aortic calcification (AAC) has not been reported before. Using data from National Health and Nutrition Examination Survey 2013-2014, we aimed to determine the relationship of WWI and AAC in adults aged ≥ 40 years. WWI was determined by dividing waist circumference by the square root of weight. AAC was measured by dual-energy X-ray absorptiometry and quantified by Kauppila scores. Severe AAC (SAAC) was defined as an AAC score > 6. We utilized weighed multivariable logistic regression and generalized additive model to explore the independent association between WWI and AAC. Threshold effects were further calculated by two-piecewise linear regression model. 3082 participants were enrolled in our analysis, of which 48.2% were male. WWI was positively associated with AAC scores (ß = 0.34, 95% CI 0.05-0.63) and exhibited a nonlinear relationship with SAAC. On the left of the breakpoint (WWI = 11.11), WWI and SAAC were positively associated (OR = 2.86, 95% CI 1.40-5.84), while no such relationship was found on the right (OR = 1.07, 95% CI 0.77-1.48). Our findings indicated that WWI may serve as a simple biomarker of AAC in US adults aged ≥ 40 years.

Exosomal STAT1 derived from high phosphorus­stimulated vascular endothelial cells induces vascular smooth muscle cell calcification via the Wnt/ß­catenin signaling pathway.

Vascular calcification is commonly observed in chronic kidney disease. The mechanism of how the calcification signal from endothelial cells is transmitted to vascular smooth muscle cells (VSMCs) remains unknown. The aim of the present study was to investigate whether exosomes from HUVECs (HUVEC­Exos) could regulate VSMC calcification and its potential signaling pathway. HUVEC­Exos were isolated from HUVECs under no phosphorus (NP) and high phosphorus (HP) conditions. Alizarin Red S staining and calcium (Ca) content analysis were carried out to detect calcification in VSMCs. Proteomics analysis was carried out to detect the differential expression of exosomal proteins. Protein and mRNA levels were measured by western blot analysis and reverse transcription­quantitative PCR (RT­qPCR). Exosomes derived from HP­HUVECs promoted the calcification of VSMCs, as assessed by Alizarin Red S staining, alkaline phosphatase activity assays, Ca content measurements and the increased expression of runt­related transcription factor 2 and osteopontin. Proteomic analysis detected the upregulation of STAT1 in HP­exosomes from HUVECs (HUVEC­Exos) compared with NP­HUVEC­Exos, which was also confirmed by western blot analysis and RT­qPCR. Inhibition of STAT1 expression in VSMCs using fludarabine or knockdown of STAT1 expression using small interfering RNA alleviated the calcification of VSMCs. Furthermore, lithium chloride (Wnt activator) reversed the protective effect of STAT1 inhibition on VSMC calcification, while Dickkopf­1 (Wnt inhibitor) exerted the opposite effect, suggesting that activation of the Wnt/ß­catenin signaling pathway was involved in STAT1­mediated VSMC calcification. In conclusion, the present results indicated that exosomal STAT1 derived from HP­treated HUVECs could promote VSMC calcification, and activation of the Wnt/ß­catenin pathway may be a potential mechanism of the VSMC calcification promoted by exosomes.

Resolvin D1 attenuates sepsis induced acute kidney injury targeting mitochondria and NF-κB signaling pathway.

Background: Acute kidney injury is a highly common and multifactorial renal disease resulting in significant morbidity and mortality, especially sepsis-induced acute kidney injury. There is no effective therapy available to treat or prevent sepsis-induced acute kidney injury. One of the specialized pro-resolving mediators, Resolvin D1 exhibits special anti-inflammatory effects in several inflammatory disease models, but there is little evidence about the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. Methods: We conducted experiments to explore the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. In vitro, human proximal tubular epithelial cells were used to test the apoptosis ratio, cell viability and reactive oxygen species level. In vivo, C57BL/6 mice were injected with lipopolysaccharide to establish a sepsis-induced acute kidney injury model. Renal function and structure, apoptosis ratio of kidney cells, mitochondrial structure and function and related protein and gene levels were assessed. Results: In vitro, the resolvin D1-treated group showed higher cell viability and lower reactive oxygen species levels and apoptosis ratios than the LPS group. In vivo, Resolvin D1 can not only improve renal function and mitochondrial function but also reduce the apoptosis ratio, while mediating mitochondrial dynamics and inhibiting NF-κB pathway. Conclusions: Resolvin D1 has a good renoprotective effect by maintaining mitochondrial dynamics and inhibiting the NF-κB pathway.

Advances in the Development of Biomaterials for Endotoxin Adsorption in Sepsis.

Sepsis, a life-threatening and intractable disease without any specific treatment, is activated by endotoxin. Some attempts at removing endotoxin to treat sepsis from the blood circulation using different hemoperfusion cartridges have been proposed recently, but they have failed to reduce the mortality of severe septic patients. This review summarizes the latest advances in the development of endotoxin adsorbents. In particular, we highlight two critical parameters for endotoxin adsorbents when they are applied in blood purification: the dissociation constant and the maximum adsorption capacity. We also discuss potential challenges and research directions for the future development of endotoxin adsorbents.

Maresin 1 Attenuates Lipopolysaccharide-Induced Acute Kidney Injury via Inhibiting NOX4/ROS/NF-κB Pathway.

Sepsis-associated acute kidney injury (S-AKI) is a common complication in hospitalized and critically ill patients, which increases the risk of multiple comorbidities and is associated with extremely high mortality. Maresin 1 (MaR1), a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid has been reported to protect against inflammation and promote the regression of acute inflammation. This study proposed to systematically investigate the renoprotective effects and potential molecular mechanism of MaR1 in septic acute kidney injury. We established a S-AKI animal model by a single intraperitoneal injection of lipopolysaccharide (LPS), 10 mg/kg, on male C57BL/6J mice. LPS-stimulated (100 µg/ml) mouse kidney tubular epithelium cells (TCMK-1) were used to simulate septic AKI in vitro. The results showed that pretreatment with MaR1 significantly reduced serum creatinine and blood urea nitrogen levels as well as tubular damage scores and injury marker neutrophil gelatinase-associated lipocalin in septic AKI mice. Meanwhile, MaR1 administration obviously diminished pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß, and MCP-1), downregulated BAX and cleaved caspase-3 expression, and upregulated BCL-2 expression in the injured kidney tissues and TCMK-1 cells. In addition, MaR1 reduced malondialdehyde production and improved the superoxide dismutase activity of renal tissues while inhibiting reactive oxygen species (ROS) production and protecting the mitochondria. Mechanistically, LPS stimulated the expression of the NOX4/ROS/NF-κB p65 signaling pathway in S-AKI kidneys, while MaR1 effectively suppressed the activation of the corresponding pathway. In conclusion, MaR1 attenuated kidney inflammation, apoptosis, oxidative stress, and mitochondrial dysfunction to protect against LPS-induced septic AKI via inhibiting the NOX4/ROS/NF-κB p65 signaling pathway.

Associations Between 25-Hydroxyvitamin D, Kidney Function, and Insulin Resistance Among Adults in the United States of America.

BACKGROUND: Although many molecular studies have tried to explore the relationship between vitamin D metabolism and kidney function, the association between 25-hydroxyvitamin D [25(OH)D] and kidney function is still controversial. Previous studies reported that low vitamin D status and decreased kidney function were associated with insulin resistance (IR). However, neither of them was confirmed by large population-based studies. This study evaluated the associations between 25(OH)D and kidney function and the associations between both of them and IR among adults in the United States of America (USA). METHODS: We analyzed 36,523 adults from the National Health and Nutrition Examination Survey (NHANES) (2001-2014). Kidney function was assessed by the estimated glomerular filtration rate (eGFR), and IR was assessed by homeostasis model assessment (HOMA-IR). All data were survey-weighted, and corresponding linear regression models were performed to examine the associations. RESULTS: The mean serum 25(OH)D levels were found to be increased in participants with decreased kidney function (eGFR <90 ml/min/1.73 m2), and each unit of decreased serum 25(OH)D concentrations predicted 0.453 ml/min/1.73 m2 (95% CI: 0.426 to 0.480, p < 0.0001) higher eGFR. In addition, each unit of decreased eGFR was associated with 0.007 higher HOMA-IR, while each unit of decreased 25(OH)D concentrations led to 0.025 higher HOMA-IR. CONCLUSIONS: Serum 25-hydroxyvitamin D concentrations were negatively associated with kidney function. IR appears in the early stage of kidney dysfunction, and both serum 25(OH)D concentrations and kidney function are negatively associated with IR. Clinicians should maintain appropriate serum 25(OH)D concentrations and doses of vitamin D supplements for different populations. The underlying mechanism of these associations still needs more research, especially the negative association between serum 25(OH)D concentrations and kidney function.

A narrative review of exosomes in vascular calcification.

Vascular calcification (VC) is the abnormal deposition of calcium, phosphorus, and other minerals in the vessel wall and can be commonly observed in diabetes, chronic kidney disease, and chronic inflammatory disease. It is closely associated with mortality from cardiovascular events. Traditionally, calcification is considered as a degenerative disease associated with the aging process, while increasing evidence has shown that the occurrence and development of calcification is an active biological process, which is highly regulated by multiple factors. The molecular mechanisms of VC have not yet been fully elucidated. Exosomes, as important transporters of substance transport and intercellular communication, have been shown to participate in VC. The regulation of VC by exosomes involves a number of complex biological processes, which occur through a variety of interaction mechanisms. However, the specific role and mechanism of exosomes in the process of VC are still not fully understood and require further study. This review will briefly describe the roles of exosomes in the process of VC including in the promotion of extracellular mineral deposits, induction of phenotypic conversion of vascular smooth muscle cells (VSMCs), transport of microRNA between cells, and regulation on autophagy and oxidative stress, with the aim of providing novel ideas for the clinical diagnosis and treatment of VC.