Potentially modifiable factors associated with health-related quality of life among people with chronic kidney disease: baseline findings from the National Unified Renal Translational Research Enterprise CKD (NURTuRE-CKD) cohort.

Background: Many non-modifiable factors are associated with poorer health-related quality of life (HRQoL) experienced by people with chronic kidney disease (CKD). We hypothesize that potentially modifiable factors for poor HRQoL can be identified among CKD patients, providing potential targets for intervention. Method: The National Unified Renal Translational Research Enterprise Chronic Kidney Disease (NURTuRE-CKD) cohort study recruited 2996 participants from nephrology centres with all stages of non-dialysis-dependent CKD. Baseline data collection for sociodemographic, anthropometric, biochemical and clinical information, including Integrated Palliative care Outcome Scale renal, Hospital Anxiety and Depression score (HADS) and the 5-level EuroQol-5D (EQ-5D-5L) as HRQoL measure, took place between 2017 and 2019. EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) were mapped to an EQ-5D-3L value set to derive index value. Multivariable mixed effects regression models, adjusted for known factors affecting HRQoL with recruitment region as a random effect, were fit to assess potentially modifiable factors associated with index value (linear) and within each dimension (logistic). Results: Among the 2958/2996 (98.7%) participants with complete EQ-5D data, 2201 (74.4%) reported problems in at least one EQ-5D-5L dimension. Multivariable linear regression identified independent associations between poorer HRQoL (EQ-5D-3L index value) and obesity (body mass index ≥30.0 kg/m2, ß -0.037, 95% CI -0.058 to -0.016, P = .001), HADS depression score ≥8 (ß -0.159, -0.182 to -0.137, P < .001), anxiety score ≥8 (ß -0.090, -0.110 to -0.069, P < .001), taking ≥10 medications (ß -0.065, -0.085 to -0.046, P < .001), sarcopenia (ß -0.062, -0.080 to -0.043, P < .001) haemoglobin <100 g/L (ß -0.047, -0.085 to -0.010, P = .012) and pain (ß -0.134, -0.152 to -0.117, P < .001). Smoking and prescription of prednisolone independently associated with problems in self-care and usual activities respectively. Renin-angiotensin system inhibitor (RASi) prescription associated with fewer problems with mobility and usual activities. Conclusion: Potentially modifiable factors including obesity, pain, depression, anxiety, anaemia, polypharmacy, smoking, steroid use and sarcopenia associated with poorer HRQoL in this cohort, whilst RASi use was associated with better HRQoL in two dimensions.

Blood pressure targets in chronic kidney disease: still no consensus.

PURPOSE OF REVIEW: Despite a strong consensus that treatment of hypertension is fundamental to strategies seeking to slow chronic kidney disease (CKD) progression and reduce the associated risk of cardiovascular events (CVE), controversy persists regarding optimal blood pressure (BP) targets. This article reviews the evidence for different targets, discusses associated controversies and suggests approaches to improve BP control. RECENT FINDINGS: Landmark clinical trials established the principle that lower BP targets are associated with slower progression of CKD in people with a greater magnitude of proteinuria and previous guidelines recommended a target BP of <130/80 mmHg for those with proteinuria. However, the Systolic Blood Pressure Intervention Trial provided new evidence that a systolic BP target of <120 mmHg was associated with a reduced risk of CVE, though there was no impact on CKD progression and there was concern about an increase in renal adverse events. Nevertheless, 2021 Kidney Disease Improving Global Outcomes guidelines recommended systolic BP <120 mmHg, though other updated guidelines did not follow this trend. All guidelines emphasise the importance of standardised BP measurement and a personalised approach. SUMMARY: An individualised and shared decision-making approach to BP target setting and management is recommended, guided by standardised BP measurement.

Associations with age and glomerular filtration rate in a referred population with chronic kidney disease: methods and baseline data from a UK multicentre cohort study (NURTuRE-CKD).

BACKGROUND: Chronic kidney disease (CKD) is common but heterogenous and is associated with multiple adverse outcomes. The National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort was established to investigate risk factors for clinically important outcomes in persons with CKD referred to secondary care. METHODS: Eligible participants with CKD stages G3-4 or stages G1-2 plus albuminuria >30 mg/mmol were enrolled from 16 nephrology centres in England, Scotland and Wales from 2017 to 2019. Baseline assessment included demographic data, routine laboratory data and research samples. Clinical outcomes are being collected over 15 years by the UK Renal Registry using established data linkage. Baseline data are presented with subgroup analysis by age, sex and estimated glomerular filtration rate (eGFR). RESULTS: A total of 2996 participants was enrolled. Median (interquartile range) age was 66 (54-74) years, eGFR 33.8 (24.0-46.6) mL/min/1.73 m2 and urine albumin to creatinine ratio 209 (33-926) mg/g; 58.5% were male. Of these participants, 1883 (69.1%) were in high-risk CKD categories. Primary renal diagnosis was CKD of unknown cause in 32.3%, glomerular disease in 23.4% and diabetic kidney disease in 11.5%. Older participants and those with lower eGFR had higher systolic blood pressure and were less likely to be treated with renin-angiotensin system inhibitors (RASi) but were more likely to receive a statin. Female participants were less likely to receive a RASi or statin. CONCLUSIONS: NURTuRE-CKD is a prospective cohort of persons who are at relatively high risk of adverse outcomes. Long-term follow-up and a large biorepository create opportunities for research to improve risk prediction and to investigate underlying mechanisms to inform new treatment development.

TES-1/Tes and ZYX-1/Zyxin protect junctional actin networks under tension during epidermal morphogenesis in the C. elegans embryo.

LIM-domain-containing repeat (LCR) proteins are recruited to strained actin filaments within stress fibers in cultured cells,1,2,3 but their roles at cell-cell junctions in living organisms have not been extensively studied. Here, we show that the Caenorhabditis elegans LCR proteins TES-1/Tes and ZYX-1/Zyxin are recruited to apical junctions during embryonic elongation when junctions are under tension. In genetic backgrounds in which embryonic elongation fails, junctional recruitment is severely compromised. The two proteins display complementary patterns of expression: TES-1 is expressed in lateral (seam) epidermal cells, whereas ZYX-1 is expressed in dorsal and ventral epidermal cells. tes-1 and zyx-1 mutant embryos display junctional F-actin defects. The loss of either protein strongly enhances morphogenetic defects in hypomorphic mutant backgrounds for cadherin/catenin complex (CCC) components. The LCR regions of TES-1 and ZYX-1 are recruited to stress fiber strain sites (SFSSs) in cultured vertebrate cells. Together, these data establish TES-1 and ZYX-1 as components of a multicellular, tension-sensitive system that stabilizes the junctional actin cytoskeleton during embryonic morphogenesis.

C. elegans srGAP is an α-catenin M domain-binding protein that strengthens cadherin-dependent adhesion during morphogenesis.

The cadherin-catenin complex (CCC) is central to embryonic development and tissue repair, yet how CCC binding partners function alongside core CCC components remains poorly understood. Here, we establish a previously unappreciated role for an evolutionarily conserved protein, the slit-robo GTPase-activating protein SRGP-1/srGAP, in cadherin-dependent morphogenetic processes in the Caenorhabditis elegans embryo. SRGP-1 binds to the M domain of the core CCC component, HMP-1/α-catenin, via its C terminus. The SRGP-1 C terminus is sufficient to target it to adherens junctions, but only during later embryonic morphogenesis, when junctional tension is known to increase. Surprisingly, mutations that disrupt stabilizing salt bridges in the M domain block this recruitment. Loss of SRGP-1 leads to an increase in mobility and decrease of junctional HMP-1. In sensitized genetic backgrounds with weakened adherens junctions, loss of SRGP-1 leads to late embryonic failure. Rescue of these phenotypes requires the C terminus of SRGP-1 but also other domains of the protein. Taken together, these data establish a role for an srGAP in stabilizing and organizing the CCC during epithelial morphogenesis by binding to a partially closed conformation of α-catenin at junctions.

Effects of olfactory stimulus on group performance and individual stress responses in university students.

Group work is essential in professional settings to encourage effective communication and optimize outcomes. Stress can reduce teamwork effectiveness and aromatherapy might be able to reduce feelings of stress/anxiety in individuals. However, it is unclear if aromatherapy impacts stress levels or performance during group activities. Therefore, we examined if essential oil exposure impacted stress responses and performance of individuals and groups during a team-based task involving a challenging medical decision. Subjects (n = 36) were part of a 3-person group (12 groups total) that completed a timed moral reasoning dilemma wearing a mask that contained a purported stimulatory essential oil (peppermint), a purported relaxing essential oil (lavender) or masks that contained neither odor (3 groups/mask type). Heart rate (HR) responses were recorded continuously before, during and after the task. The time to complete the task, decision making during the task, and subject's perceptions of the task were also recorded. Control subjects and subjects exposed to peppermint demonstrated a significant stress-induced increase in HR during the group task. However, subjects exposed to lavender demonstrated a significantly attenuated HR. Subjects in the control group who perceived high stress levels during the task demonstrated further elevations in HR than those not reporting stress, however, this pattern was not observed in subjects exposed to either essential oil. Groups did not differ in the time required to complete the task although only the groups exposed to lavender used decision making consistent with medical practice. Therefore, exposure to lavender was associated with differential physiological responses during a stressful group task, potentially due to olfactory system stimulation of anxiolytic and/or trust promoting central nervous system pathways. Aromatherapy might be a useful tool in group settings to mitigate the impact of stress and improve group performance.

A Feasibility Study of Non-Invasive Continuous Estimation of Brachial Pressure Derived From Arterial and Venous Lines During Dialysis.

Objective: Intradialytic haemodynamic instability is a significant clinical problem, leading to end-organ ischaemia and contributing to morbidity and mortality in haemodialysis patients. Non-invasive continuous blood pressure monitoring is not currently part of routine practice but may aid detection and prevention of significant falls in blood pressure during dialysis. Brachial blood pressure is currently recorded intermittently during haemodialysis via a sphygmomanometer. Current methods of continuous non-invasive blood pressure monitoring tend to restrict movement, can be sensitive to external disturbances and patient movement, and can be uncomfortable for the wearer. Additionally, poor patient blood circulation can lead to unreliable measurements. In this feasibility study we performed an initial validation of a novel method and associated technology to continuously estimate blood pressure using pressure sensors in the extra-corporeal dialysis circuit, which does not require any direct contact with the person receiving dialysis treatment. Method: The paper describes the development of the measurement system and subsequent in vivo patient feasibility study with concurrent measurement validation by Finapres Nova physiological measurement device. Real-time physiological data is collected over the entire period of (typically 4-hour) dialysis treatment. Results: We identify a quasi-linear mathematical function to describe the relationship between arterial line pressure and brachial artery BP, which is confirmed in a patient study. The results from this observational study suggest that it is feasible to derive a continuous measurement of brachial pressure from continuous measurements of arterial and venous line pressures via an empirically based and updated mathematical model. Conclusion: The methodology presented requires no interfacing to proprietary dialysis machine systems, no sensors to be attached to the patient directly, and is robust to patient movement during treatment and also to the effects of the cyclical pressure waveforms induced by the hemodialysis peristaltic blood pump. This represents a key enabling factor to the development of a practical continuous blood pressure monitoring device for dialysis patients.

Long-Term Outcomes in Patients with Acute Kidney Injury.

The long-term sequelae of AKI have received increasing attention so that its associations with a number of adverse outcomes, including higher mortality and development of CKD, are now widely appreciated. These associations take on particular importance when considering the high incidence of AKI, with a lack of proven interventions and uncertainties around optimal care provision meaning that the long-term sequelae of AKI present a major unmet clinical need. In this review, we examine the published data that inform our current understanding of long-term outcomes following AKI and discuss potential knowledge gaps, covering long-term mortality, CKD, progression to ESKD, proteinuria, cardiovascular events, recurrent AKI, and hospital readmission.

Sex differences in heart rate responses to occupational stress.

Cardiovascular disease (CVD) remains the leading cause of disease burden globally and chronic stress is associated with increased risk of CVD. Recognition of chronic occupational stressors as a potential contributor to CVD highlights the need to recognize and prevent stress during work. The ubiquity of wearable technology devices to monitor health provides a new opportunity to noninvasively examine the cardiovascular system throughout a work shift. In the current study, we examined changes in heart rate (HR) during a work shift in a retail store setting using 23 healthy female and male subjects that differed in their physical fitness status. Subjects had their HR tracked via an Apple Watch during three typical work shifts. The results demonstrated an increase in HR during a work shift to a level observed during a moderate stressor (resting HR = 83.2 BPM ± 7.8; highest HR mean = 109.1 BPM ± 11.7; p < .0001). Female subjects demonstrated a significantly elevated maximum HR, a larger change in HR, and a larger percent change in HR compared with males (all p < .05). Physical activity status did not influence the observed changes in HR for females or males. Neither the time of day the work shift occurred nor the length of the shift modulated the observed pattern of HR changes. Collectively, our findings demonstrate the potential for wearables in biomedical research and personalized health.

The adhesion modulation domain of Caenorhabditis elegans α-catenin regulates actin binding during morphogenesis.

Maintaining tissue integrity during epidermal morphogenesis depends on α-catenin, which connects the cadherin complex to F-actin. We show that the adhesion modulation domain (AMD) of Caenorhabditis elegans HMP-1/α-catenin regulates its F-actin-binding activity and organization of junctional-proximal actin in vivo. Deleting the AMD increases F-actin binding in vitro and leads to excess actin recruitment to adherens junctions in vivo. Reducing actin binding through a compensatory mutation in the C-terminus leads to improved function. Based on the effects of phosphomimetic and nonphosphorylatable mutations, phosphorylation of S509, within the AMD, may regulate F-actin binding. Taken together, these data establish a novel role for the AMD in regulating the actin-binding ability of an α-catenin and its proper function during epithelial morphogenesis.

Mind the (sr)GAP - roles of Slit-Robo GAPs in neurons, brains and beyond.

The Slit-Robo GTPase-activating proteins (srGAPs) were first identified as potential Slit-Robo effectors that influence growth cone guidance. Given their N-terminal F-BAR, central GAP and C-terminal SH3 domains, srGAPs have the potential to affect membrane dynamics, Rho family GTPase activity and other binding partners. Recent research has clarified how srGAP family members act in distinct ways at the cell membrane, and has expanded our understanding of the roles of srGAPs in neuronal and non-neuronal cells. Gene duplication of the human-specific paralog of srGAP2 has resulted in srGAP2 family proteins that may have increased the density of dendritic spines and promoted neoteny of the human brain during crucial periods of human evolution, underscoring the importance of srGAPs in the unique sculpting of the human brain. Importantly, srGAPs also play roles outside of the nervous system, including during contact inhibition of cell movement and in establishing and maintaining cell adhesions in epithelia. Changes in srGAP expression may contribute to neurodevelopmental disorders, cancer metastasis and inflammation. As discussed in this Review, much remains to be discovered about how this interesting family of proteins functions in a diverse set of processes in metazoans and the functional roles srGAPs play in human disease.

CDC-42 Orients Cell Migration during Epithelial Intercalation in the Caenorhabditis elegans Epidermis.

Cell intercalation is a highly directed cell rearrangement that is essential for animal morphogenesis. As such, intercalation requires orchestration of cell polarity across the plane of the tissue. CDC-42 is a Rho family GTPase with key functions in cell polarity, yet its role during epithelial intercalation has not been established because its roles early in embryogenesis have historically made it difficult to study. To circumvent these early requirements, in this paper we use tissue-specific and conditional loss-of-function approaches to identify a role for CDC-42 during intercalation of the Caenorhabditis elegans dorsal embryonic epidermis. CDC-42 activity is enriched in the medial tips of intercalating cells, which extend as cells migrate past one another. Moreover, CDC-42 is involved in both the efficient formation and orientation of cell tips during cell rearrangement. Using conditional loss-of-function we also show that the PAR complex functions in tip formation and orientation. Additionally, we find that the sole C. elegans Eph receptor, VAB-1, functions during this process in an Ephrin-independent manner. Using epistasis analysis, we find that vab-1 lies in the same genetic pathway as cdc-42 and is responsible for polarizing CDC-42 activity to the medial tip. Together, these data establish a previously uncharacterized role for polarized CDC-42, in conjunction with PAR-6, PAR-3 and an Eph receptor, during epithelial intercalation.

Macroglobulin complement-related encodes a protein required for septate junction organization and paracellular barrier function in Drosophila.

Polarized epithelia play crucial roles as barriers to the outside environment and enable the formation of specialized compartments for organs to carry out essential functions. Barrier functions are mediated by cellular junctions that line the lateral plasma membrane between cells, principally tight junctions in vertebrates and septate junctions (SJs) in invertebrates. Over the last two decades, more than 20 genes have been identified that function in SJ biogenesis in Drosophila, including those that encode core structural components of the junction such as Neurexin IV, Coracle and several claudins, as well as proteins that facilitate the trafficking of SJ proteins during their assembly. Here we demonstrate that Macroglobulin complement-related (Mcr), a gene previously implicated in innate immunity, plays an essential role during embryonic development in SJ organization and function. We show that Mcr colocalizes with other SJ proteins in mature ectodermally derived epithelial cells, that it shows interdependence with other SJ proteins for SJ localization, and that Mcr mutant epithelia fail to form an effective paracellular barrier. Tissue-specific RNA interference further demonstrates that Mcr is required cell-autonomously for SJ organization. Finally, we show a unique interdependence between Mcr and Nrg for SJ localization that provides new insights into the organization of the SJ. Together, these studies demonstrate that Mcr is a core component of epithelial SJs and also highlight an interesting relationship between innate immunity and epithelial barrier functions.