Cardiovascular Functional Changes in Chronic Kidney Disease:Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease

Uremic serum-induced calcification of human aortic smooth muscle cells is a regulated process involving Klotho and RUNX2

© 2019 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).Vascular calcification (VC) is common in subjects with chronic kidney disease (CKD) and is associated with increased cardiovascular risk. It is an active process involving transdifferentiation of arterial smooth muscle cells (SMCs) into osteogenic phenotype. We investigated the ability of serum from CKD subjects to induce calcification in human SMCs in vitro (calcific potential of sera: CP), and associated changes in expression of Runt-related transcription factor 2 (RUNX2), SM22a, and Klotho. Sera from subjects with CKD (18 stage 3, 17 stage 4/5, and 29 stage 5D) and 20 controls were added to human cultured SMCs and CP quantified. The CP of CKD sera was greater (P>0.01) than that of controls, though not influenced by CKD stage. Modification of diet in renal disease estimated glomerular filtration rate (MDRD-4 eGFR) (P>0.001), serum phosphate (P=0.042), receptor activator of nuclear factor ?appa-B ligand (RANKL) (P=0.001), parathyroid hormone (PTH) (P=0.014), and high-density lipoprotein (HDL)/cholesterol ratio (P=0.026) were independent predictors of CP accounting for 45% of variation. Adding calcification buffer (CB: calcium chloride [7 mM] and β-glycerophosphate [7 mM]) increased the CP of control sera to approximate that of CKD sera. CP of CKD sera was unchanged. CKD sera increased RUNX2 expression (P>0.01) in human SMCs and decreased SM22a expression (P>0.05). Co-incubating control but not CKD serum with CB further increased RUNX2 expression (P>0.01). Both SM22a and Klotho expression decreased significantly (P>0.01) in the presence of CKD serum, and were virtually abolished with stage 5D sera. These findings support active regulation by CKD serum of in vitro VC by induction of RUNX2 and suppression of SM22a and Klotho.Peer reviewe

Regional variability in use of a novel assessment of thoracolumbar spine fractures: United States versus international surgeons

<p>Abstract</p> <p>Background</p> <p>Considerable variability exists in clinical approaches to thoracolumbar fractures. Controversy in evaluation and nomenclature contribute to this confusion, with significant differences found between physicians, between different specialties, and in different geographic regions. A new classification system for thoracolumbar injuries, the Thoracolumbar Injury Severity Score (TLISS), was recently described by Vaccaro. No assessment of regional differences has been described. We report regional variability in use of the TLISS system between United States and non-US surgeons.</p> <p>Methods</p> <p>Twenty-eight spine surgeons (8 neurosurgeons and 20 orthopedic surgeons) reviewed 56 clinical thoracolumbar injury case histories, which included pertinent imaging studies. Cases were classified and scored using the TLISS system. After a three month period, the case histories were re-ordered and the physicians repeated the exercise; 22 physicians completed both surveys and were used to assess intra-rater reliability. The reliability and treatment validity of the TLISS was assessed. Surgeons were grouped into US (n = 15) and non-US (n = 13) cohorts. Inter-rater (both within and between different geographic groups) and intra-rater reliability was assessed by percent agreement, Cohen's kappa, kappa with linear weighting, and Spearman's rank-order correlation.</p> <p>Conclusion</p> <p>Non-US surgeons were found to have greater inter-rater reliability in injury mechanism, while agreement on neurological status and posterior ligamentous complex integrity tended to be higher among US surgeons. Inter-rater agreement on management was moderate, although it tended to be higher in US-surgeons. Inter-rater agreement between US and non-US surgeons was similar to within group inter-rater agreement for all categories. While intra-rater agreement for mechanism tended to be higher among US surgeons, intra-rater reliability for neurological status and PLC was slightly higher among non-US surgeons. Intra-rater reliability for management was substantial in both US and non-US surgeons. The TLISS incorporates generally accepted features of spinal injury assessment into a simple patient evaluation tool. The management recommendation of the treatment algorithm component of the TLISS shows good inter-rater and substantial intra-rater reliability in both non-US and US based spine surgeons. The TLISS may improve communication between health providers and may contribute to more efficient management of thoracolumbar injuries.</p

Surgical Decision Making for Unstable Thoracolumbar Spine Injuries: Results of a Consensus Panel Review by the Spine Trauma Study Group

Objectives: The optimal surgical approach and treatment of unstable thoracolumbar spine injuries are poorly defined owing to a lack of widely accepted level I clinical literature. This lack of evidence based standards has led to varied practice patterns based on individual surgeon preferences. The purpose of this study was to survey the leaders in the field of spine trauma to define the major characteristics of thoracolumbar injuries that influence their surgical decision making. In the absence of good scientific data, expert consensus opinions may provide surgeons with a practical framework to guide therapy and to conduct future research. Methods: A panel of 22 leading spinal surgeons from 20 level I trauma centers in seven countries met to discuss the indications for surgical approach selection in unstable thoracolumbar injuries. Injuries were presented to the surgeons in a case scenario survey format. Preferred surgical approaches to the clinical scenarios were tabulated and comments weighed. Results: All members of the panel agreed that three independent characteristics of thoracolumbar injuries carry primary importance in surgical decision making: the injury morphology, the neurologic status of the patient, and the integrity of the posterior ligaments. Six clinical scenarios based on the neurologic status of the patient (intact, incomplete, or complete) and on the status of the posterior ligamentous complex (intact or disrupted) were created, and consensus treatment approaches were described. Additional circumstances capable of altering the treatments were acknowledged. Conclusions: Decision making for the surgical treatment of thoracolumbar injuries is largely dependent on three patient characteristics: injury morphology, neurologic status, and posterior ligament integrity. A logical and practical decision-making process based on these characteristics may guide treatment even for the most complicated fracture patterns

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity

Background The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross‐sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low‐frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min −1 ·1.73 m −2 ), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage &gt;12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min −1 ·kg −1 ) compared with predialysis (22.7 [5.2] mL·min −1 ·kg −1 ; P &lt;0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index ( P &lt;0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage &gt;12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min −1 ·kg −1 ) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min −1 ·kg −1 ; P =0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low‐risk New York Heart Association class I and higher‐risk New York Heart Association class II to IV heart failure

Thoracolumbar injury classification and severity score: a new paradigm for the treatment of thoracolumbar spine trauma

BACKGROUND: Contemporary understanding of the biomechanics, natural history, and methods of treating thoracolumbar spine injuries continues to evolve. Current classification schemes of these injuries, however, can be either too simplified or overly complex for clinical use. METHODS: The Spine Trauma Group was given a survey to identify similarities in treatment algorithms for common thoracolumbar injuries, as well as to identify characteristics of injury that played a key role in the decision-making process. RESULTS: Based on the survey, the Spine Trauma Group has developed a classification system and an injury severity score (thoracolumbar injury classification and severity score, or TLICS), which may facilitate communication between physicians and serve as a guideline for treating these injuries. The classification system is based on the morphology of the injury, integrity of the posterior ligamentous complex, and neurological status of the patient. Points are assigned for each category, and the final total points suggest a possible treatment option. CONCLUSIONS: The usefulness of this new system will have to be proven in future studies investigating inter- and intraobserver reliability, as well as long-term outcome studies for operative and nonoperative treatment methods

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000

Spiral-Wave Turbulence and Its Control in the Presence of Inhomogeneities in Four Mathematical Models of Cardiac Tissue

Regular electrical activation waves in cardiac tissue lead to the rhythmic contraction and expansion of the heart that ensures blood supply to the whole body. Irregularities in the propagation of these activation waves can result in cardiac arrhythmias, like ventricular tachycardia (VT) and ventricular fibrillation (VF), which are major causes of death in the industrialised world. Indeed there is growing consensus that spiral or scroll waves of electrical activation in cardiac tissue are associated with VT, whereas, when these waves break to yield spiral- or scroll-wave turbulence, VT develops into life-threatening VF: in the absence of medical intervention, this makes the heart incapable of pumping blood and a patient dies in roughly two-and-a-half minutes after the initiation of VF. Thus studies of spiral- and scroll-wave dynamics in cardiac tissue pose important challenges for in vivo and in vitro experimental studies and for in silico numerical studies of mathematical models for cardiac tissue. A major goal here is to develop low-amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of inhomogeneities that occur commonly in cardiac tissue. We present a detailed and systematic study of spiral- and scroll-wave turbulence and spatiotemporal chaos in four mathematical models for cardiac tissue, namely, the Panfilov, Luo-Rudy phase 1 (LRI), reduced Priebe-Beuckelmann (RPB) models, and the model of ten Tusscher, Noble, Noble, and Panfilov (TNNP). In particular, we use extensive numerical simulations to elucidate the interaction of spiral and scroll waves in these models with conduction and ionic inhomogeneities; we also examine the suppression of spiral- and scroll-wave turbulence by low-amplitude control pulses. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such inhomogeneities. We also study two types of control schemes that have been suggested for the control of spiral turbulence, via low amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control schemes in the presence of inhomogeneities. We find that a local pulsing scheme does not suppress spiral turbulence in the presence of inhomogeneities; but a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London