Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Trauma-focused therapy in early psychosis: results of a feasibility randomized controlled trial of EMDR for psychosis (EMDRp) in early intervention settings.

BACKGROUND: Trauma is prevalent amongst early psychosis patients and associated with adverse outcomes. Past trials of trauma-focused therapy have focused on chronic patients with psychosis/schizophrenia and comorbid Post-Traumatic Stress Disorder (PTSD). We aimed to determine the feasibility of a large-scale randomized controlled trial (RCT) of an Eye Movement Desensitization and Reprocessing for psychosis (EMDRp) intervention for early psychosis service users. METHODS: A single-blind RCT comparing 16 sessions of EMDRp + TAU v. TAU only was conducted. Participants completed baseline, 6-month and 12-month post-randomization assessments. EMDRp and trial assessments were delivered both in-person and remotely due to COVID-19 restrictions. Feasibility outcomes were recruitment and retention, therapy attendance/engagement, adherence to EMDRp treatment protocol, and the 'promise of efficacy' of EMDRp on relevant clinical outcomes. RESULTS: Sixty participants (100% of the recruitment target) received TAU or EMDR + TAU. 83% completed at least one follow-up assessment, with 74% at 6-month and 70% at 12-month. 74% of EMDRp + TAU participants received at least eight therapy sessions and 97% rated therapy sessions demonstrated good treatment fidelity. At 6-month, there were signals of promise of efficacy of EMDRp + TAU v. TAU for total psychotic symptoms (PANSS), subjective recovery from psychosis, PTSD symptoms, depression, anxiety, and general health status. Signals of efficacy at 12-month were less pronounced but remained robust for PTSD symptoms and general health status. CONCLUSIONS: The trial feasibility criteria were fully met, and EMDRp was associated with promising signals of efficacy on a range of valuable clinical outcomes. A larger-scale, multi-center trial of EMDRp is feasible and warranted.

Intradialytic techniques for automatic and everyday access monitoring.

Vascular access dysfunction is associated with reduced delivery of dialysis, unplanned admissions, patient symptoms, and loss of access, making assessment of vascular access a fundamental part of routine care in dialysis. Clinical trials to predict the risk of access thrombosis based on accepted reference methods of access performance have been disappointing. Reference methods are time-consuming, affect the delivery of dialysis, and therefore cannot repeatedly be used with every dialysis session. There is now a new focus on data continuously and regularly collected with every dialysis treatment, directly or indirectly associated with access function, and without interrupting or affecting the delivered dose of dialysis. This narrative review will focus on techniques that can be used continuously or intermittently during dialysis, taking advantage of methods integrated into the dialysis machine and which do not affect the delivery of dialysis. Examples include extracorporeal blood flow, dynamic line pressures, effective clearance, dose of delivered dialysis, and recirculation which are all routinely measured on most modern dialysis machines. Integrated information collected throughout every dialysis session and analyzed by expert systems and machine learning has the potential to improve the identification of accesses at risk of thrombosis.

Bio-impedance spectroscopy added to a fluid management protocol does not improve preservation of residual kidney function in incident hemodialysis patients in a randomized controlled trial.

Avoiding excessive dialysis-associated volume depletion may help preserve residual kidney function (RKF). To establish whether knowledge of the estimated normally hydrated weight from bioimpedance measurements (BI-NHW) when setting the post-hemodialysis target weight (TW) might mitigate rate of loss of RKF, we undertook an open label, randomized controlled trial in incident patients receiving HD, with clinicians and patients blinded to bioimpedance readings in controls. A total of 439 patients with over 500 ml urine/day or residual GFR exceeding 3 ml/min/1.73m2 were recruited from 34 United Kingdom centers and randomized 1:1, stratified by center. Fluid assessments were made for up to 24 months using a standardized proforma in both groups, supplemented by availability of BI-NHW in the intervention group. Primary outcome was time to anuria, analyzed using competing-risk survival models adjusted for baseline characteristics, by intention to treat. Secondary outcomes included rate of RKF decline (mean urea and creatinine clearance), blood pressure and patient-reported outcomes. There were no group differences in cause-specific hazard rates of anuria (0.751; 95% confidence interval (0.459, 1.229)) or sub-distribution hazard rates (0.742 (0.453, 1.215)). RKF decline was markedly slower than anticipated, pooled linear rates in year 1: -0.178 (-0.196, -0.159)), year 2: -0.061 (-0.086, -0.036)) ml/min/1.73m2/month. Blood pressure and patient-reported outcomes did not differ by group. The mean difference agreement between TW and BI-NHW was similar for both groups, Bioimpedance: -0.04 kg; Control: -0.25 kg. Thus, use of a standardized clinical protocol for fluid assessment when setting TW is associated with excellent preservation of RKF. Hence, bioimpedance measurements are not necessary to achieve this.

Patients' perspectives of fluid management: A multicentre comparative study of home and incentre haemodialysis.

BACKGROUND: There is increasing worldwide interest in person-centred care in haemodialysis and home haemodialysis (HHD). Intradialytic fluid management is a vital component of haemodialysis, and often a shared decision, yet patients' perspectives and experience of related decisions are largely unexplored. OBJECTIVES: To explore the perspectives of patients receiving home or incentre haemodialysis (IHD), in relation to intradialytic fluid management. DESIGN: A multicentre cross-sectional survey. PARTICIPANTS: Eight hundred and thirty-nine patients receiving IHD and 99 patients receiving HHD, across six English renal units. MEASUREMENTS: Self-reported measures of understanding, experiences and control of fluid management, and willingness to achieve target weight. An objective test of patients' ability to relate common signs and symptoms to fluid overload or excessive ultrafiltration. RESULTS: Patients receiving HHD had greater knowledge than those receiving IHD (66.1% vs. 42.3%, p < 0.001) about causes of common signs and symptoms which remained when controlling for age, education and years since beginning haemodialysis. Patients receiving HHD felt more in control of and had greater self-reported adherence to fluid management (p < 0.01), yet knowledge gaps existed in both cohorts. CONCLUSIONS: Greater patient knowledge and its practice in HHD may contribute to improved fluid balance and outcomes. Whilst patient selection may contribute towards these differences, the training patients receive when opting for HHD and subsequent experience are likely to be key contributing factors. Integrating aspects of education on fluid management from HHD training programmes should be considered in IHD, and further targeted, robust education remains an unmet need.

Measurement and mobilisation of localised oedema in haemodialysis.

BACKGROUND: The presence of localised oedema can make measurement and removal of excess fluid in haemodialysis challenging. OBJECTIVES: To evaluate (i) the effectiveness of intermittent pneumatic compression and neuromuscular electrical stimulation at mobilising oedema and (ii) the impact of localised fluid on bioimpedance measured fluid status. DESIGN: A single centre, cross-over study design. Participants were monitored weekly during mid-week dialysis sessions. Four sessions with each of the interventions and no interventions, with washout periods between, were included. PARTICIPANTS: Six participants with lower limb oedema and established on haemodialysis for at least 3 months. MEASUREMENTS: The effectiveness of mobilising oedema and improving haemodynamic stability was assessed by: reduction in ankle circumference; ultrafiltration volume achieved; blood pressure changes; participant symptoms and achievement of target weight. The impact of localised fluid on bioimpedance measurements was assessed by comparing measurements across affected tissue with measurements avoiding the site of oedema. RESULTS: There were no differences in ultrafiltration volumes, achievement of target weight, participant symptoms or reductions in ankle circumference and systolic blood pressure between intermittent pneumatic compression and neuromuscular electrical stimulation sessions compared to control sessions. Measurements of fluid overload with bioimpedance were 1.7 and 1.8 L higher when measuring across oedematous tissue compared to non-oedematous tissue. CONCLUSIONS: We were unable to demonstrate improved mobilisation of fluid in the participant's lower limb, though there was a low number of study participants and notable interindividual variation observed. Bioimpedance offers potential for monitoring fluid management in individuals with lower limb oedema but specific protocols are necessary.

Establishing electroporation thresholds for targeted cell specific cardiac ablation in a 2D culture model.

BACKGROUND: Irreversible electroporation has emerged as a new modality to overcome issues associated with other energy sources for cardiac ablation. Strong evidence on the optimal, effective, and selective voltage threshold is lacking for both in vitro and preclinical in vivo studies. The aim of this study is to examine the optimal threshold for selective cell ablation on cardiac associated cell types. METHODS: Conventional monophasic and biphasic pulses of different field strength were delivered in a monolayer culture system of cardiomyocytes, neurons, and adipocytes. The dynamics of cell death mechanisms were examined at different time points. RESULTS: Neurons exhibit higher susceptibility to electroporation and cell death at higher field strength of 1250 V/cm in comparison to cardiomyocytes. Cardiac adipocytes showed lower susceptibility to electroporation in comparison to other cell types. A significant proportion of cardiomyocytes recovered after 24 h postelectroporation, while neuronal cell death remained consistent but with a significant delayed cell death at a higher voltage threshold. Caspase 3/7 activity was observed in both cardiomyocytes and neurons, with a higher level of activity in cardiomyocytes in response to electroporation. Biphasic and monophasic pulses showed no significant difference in both cell types, and significantly lower cell death in neurons when inter pulse interval was reduced. CONCLUSIONS: This study presents important findings on the differences in the susceptibility of neurons and cardiomyocytes to irreversible electroporation. Cell type alone yielded selective and different dynamics in terms of the evolution and signaling mechanism of cell death in response to electroporation.

Bioimpedance Indices of Fluid Overload and Cardiorenal Outcomes in Heart Failure and Chronic Kidney Disease: a Systematic Review.

BACKGROUND: Bioimpedance-based estimates of fluid overload have been widely studied and systematically reviewed in populations of those undergoing dialysis, but data from populations with heart failure or nondialysis chronic kidney disease (CKD) have not. METHODS AND RESULTS: We conducted a systematic review of studies using whole-body bioimpedance from populations with heart failure and nondialysis CKD that reported associations with mortality, cardiovascular outcomes and/or CKD progression. We searched MEDLINE, Embase databases and the Cochrane CENTRAL registry from inception to March 14, 2022. We identified 31 eligible studies: 20 heart failure and 11 CKD cohorts, with 2 studies including over 1000 participants. A wide range of various bioimpedance methods were used across the studies (heart failure: 8 parameters; CKD: 6). Studies generally reported positive associations, but between-study differences in bioimpedance methods, fluid overload exposure definitions and modeling approaches precluded meta-analysis. The largest identified study was in nondialysis CKD (Chronic Renal Insufficiency Cohort, 3751 participants), which reported adjusted hazard ratios (95% confidence intervals) for phase angle < 5.59 vs ≥ 6.4 of 2.02 (1.67-2.43) for all-cause mortality; 1.80 (1.46-2.23) for heart failure events; and 1.78 (1.56-2.04) for CKD progression. CONCLUSIONS: Bioimpedance indices of fluid overload are associated with risk of important cardiorenal outcomes in heart failure and CKD. Facilitation of more widespread use of bioimpedance requires consensus on the optimum device, standardized analytical methods and larger studies, including more detailed characterization of cardiac and renal phenotypes.

Monitoring residual kidney function in haemodialysis patients using timed urine collections: validation of the use of estimated blood results to calculate GFR.

Objective. With growing recognition of the benefits of preserving residual kidney function (RKF) and use of incremental treatment regimes, the incentive to measure residual clearance in haemodialysis patients is increasing. Interdialytic urine collections used to monitor RKF in research studies are considered impractical in routine care, partly due to the requirement for blood samples before and after the collection. Plasma solute levels can be estimated if patients are in 'steady state', where urea and creatinine concentrations increase at a constant rate between dialysis sessions and are reduced by a constant ratio at each session. Validation of the steady state assumption would allow development of simplified protocols for urine collections in HD patients.Approach. Equations were derived for estimating plasma urea and creatinine at the start or end of the interdialytic interval for patients in steady state. Data collected during the BISTRO study was used to assess the agreement between measured and estimated plasma levels and the effect of using estimated levels on the calculated glomerular filtration rate (GFR).Main results. The mean difference between GFR calculated with estimated plasma levels for the HD session after the collection and a full set of measured levels was 2.0% (95% limits of agreement -10.7% to +14.7%,N = 316). Where plasma levels for the session before the collection were estimated, the mean difference was 1.2% (limits of agreement -10.3% to +7.9%,N = 275).Significance. Using estimated levels for one session led to a clinically significant difference in the calculated GFR for less than 3% of the collections studied. This indicates that the steady state assumption can be used to estimate solute levels when determining GFR from timed urine collections. A pragmatic approach to monitoring RKF in HD would be for patients to collect for approximately 24 h before routine bloods are taken.

Cardiac MRI e-prime predicts myocardial late gadolinium enhancement and diastolic dysfunction in hypertrophic cardiomyopathy.

BACKGROUND: Myocardial fibrosis leads to diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). OBJECTIVES: To evaluate a manual method of measuring mitral annular relaxation velocity (termed cardiac MRI e') as a measure of diastolic dysfunction on routine cardiac MRI and its relationship with myocardial late-gadolinium enhancement (LGE) and feature tracking measures of diastolic dysfunction in patients with HCM. METHODS: CMR e', feature tracking measures of diastolic function, left atrial, left ventricular (LV) parameters and LGE were retrospectively measured in 75 patients with HCM (mean age, 54.7 years ± 15.3, 54 men). Multivariate regression and partial Spearman correlations were performed. RESULTS: Cardiac MRI e' measures correlated with LGE (r = 0.49, P < 0.001) and multiple feature tracking measures of diastolic function, adjusted for patient demographics, left atrial and left ventricular parameters. Cardiac MRI e' measures were independently predictive of LGE ≥ 10% (mean total cardiac MRI e': LGE < 10% vs LGE ≥ 10% was 3.5 cm/s vs. 1.7 cm/s, P < 0.001). Superior CMR e' had an AUC of 0.79 [95%CI 0.66-0.92, P < 0.0001]) in predicting patients with LGE ≥ 10% and a cutoff of 1.7 cm/s resulted in a sensitivity and specificity of 81.0% and 78.0% respectively. CONCLUSION: Cardiac MRI e' is a manual measure of LV diastolic dysfunction acquired on routine cardiac MRI without specialized software and is an independent predictor of LGE ≥ 10% and diastolic dysfunction in HCM.

Establishing Irreversible Electroporation Electric Field Potential Threshold in A Suspension In Vitro Model for Cardiac and Neuronal Cells.

AIMS: Irreversible electroporation is an ablation technique being adapted for the treatment of atrial fibrillation. Currently, there are many differences reported in the in vitro and pre-clinical literature for the effective voltage threshold for ablation. The aim of this study is a direct comparison of different cell types within the cardiovascular system and identification of optimal voltage thresholds for selective cell ablation. METHODS: Monophasic voltage pulses were delivered in a cuvette suspension model. Cell viability and live-dead measurements of three different neuronal lines, cardiomyocytes, and cardiac fibroblasts were assessed under different voltage conditions. The immediate effects of voltage and the evolution of cell death was measured at three different time points post ablation. RESULTS: All neuronal and atrial cardiomyocyte lines showed cell viability of less than 20% at an electric field of 1000 V/cm when at least 30 pulses were applied with no significant difference amongst them. In contrast, cardiac fibroblasts showed an optimal threshold at 1250 V/cm with a minimum of 50 pulses. Cell death overtime showed an immediate or delayed cell death with a proportion of cell membranes re-sealing after three hours but no significant difference was observed between treatments after 24 h. CONCLUSIONS: The present data suggest that understanding the optimal threshold of irreversible electroporation is vital for achieving a safe ablation modality without any side-effect in nearby cells. Moreover, the evolution of cell death post electroporation is key to obtaining a full understanding of the effects of IRE and selection of an optimal ablation threshold.

Leadless left ventricular endocardial pacing for CRT upgrades in previously failed and high-risk patients in comparison with coronary sinus CRT upgrades.

AIMS: Cardiac resynchronization therapy (CRT) upgrades may be less likely to improve following intervention. Leadless left ventricular (LV) endocardial pacing has been used for patients with previously failed CRT or high-risk upgrades. We compared procedural and long-term outcomes in patients undergoing coronary sinus (CS) CRT upgrades with high-risk and previously failed CRT upgrades undergoing LV endocardial upgrades. METHOD AND RESULTS: Prospective consecutive CS upgrades between 2015 and 2019 were compared with those undergoing WiSE-CRT implantation. Cardiac resynchronization therapy response at 6 months was defined as improvement in clinical composite score (CCS) and a reduction in LV end-systolic volume (LVESV) ≥15%. A total of 225 patients were analysed; 121 CS and 104 endocardial upgrades. Patients receiving WiSE-CRT tended to have more comorbidities and were more likely to have previous cardiac surgery (30.9% vs. 16.5%; P = 0.012), hypertension (59.2% vs. 34.7%; P < 0.001), chronic obstructive airways disease (19.4% vs. 9.9%; P = 0.046), and chronic kidney disease (46.4% vs. 21.5%; P < 0.01) but similar LV ejection fraction (30.0 ± 8.3% vs. 29.5 ± 8.6%; P = 0.678). WiSE-CRT upgrades were successful in 97.1% with procedure-related mortality in 1.9%. Coronary sinus upgrades were successful in 97.5% of cases with a 2.5% rate of CS dissection and 5.6% lead malfunction/displacement. At 6 months, 91 WiSE-CRT upgrades and 107 CS upgrades had similar improvements in CCS (76.3% vs. 68.5%; P = 0.210) and reduction in LVESV ≥15% (54.2% vs. 56.3%; P = 0.835). CONCLUSION: Despite prior failed upgrades and high-risk patients with more comorbidities, WiSE-CRT upgrades had high rates of procedural success and similar improvements in CCS and LV remodelling with CS upgrades.

An assessment of radiation use, knowledge and concerns in trainee cardiologists in Ireland.

OBJECTIVE: To evaluate knowledge, routine use and concerns of trainee cardiologists in the Republic of Ireland regarding radiation use in the cardiac catheterization laboratory. METHODS: We handed out a Radiation Questionnaire to cardiology trainees in February 2020 at the Irish Cardiac Society "Spring Meeting". The questionnaire assessed radiation protection use amongst trainees and tested knowledge of X-ray basics. RESULTS: Many trainees report inadequate access to properly sized lead protection, and infrequent dosimeter usage. Over one-third of trainees report musculoskeletal issues from wearing leads, the majority of whom use correct size lead <60% of the time.33.3% report radiation concerns will affect their decision making regarding subspeciality training, but notably 83.3% of females and only 19% of males surveyed report this, showing this is a bigger issue for females in cardiology. Less than half of trainees feel adequately educated about radiation. CONCLUSION: Our assessment show deficiencies in the provision and use of personal protective equipment to trainees, highlights extra radiation concerns of female cardiology trainees, and notes gaps in knowledge in radiation use. ADVANCES IN KNOWLEDGE: Our assessment highlights deficiencies in the education of cardiology trainees regarding ionizing radiation, and suggests this area needs to be improved upon.

Patient perspectives of target weight management and ultrafiltration in haemodialysis: a multi-center survey.

BACKGROUND: Decisions around planned ultrafiltration volumes are the only part of the haemodialysis prescription decided upon at every session. Removing too much fluid or too little is associated with both acute symptoms and long-term outcomes. The degree to which patients engage with or influence decision-making is not clear. We explored patient perspectives of prescribing ultrafiltration volumes, their understanding of the process and engagement with it. METHODS: A questionnaire developed for this study was administered to 1077 patients across 10 UK Renal Units. Factor analysis reduced the dataset into factors representing common themes. Relationships between survey results and factors were investigated using regression models. ANCOVA was used to explore differences between Renal Units. RESULTS: Patients generally felt in control of their fluid management and that they were given the final say on planned ultrafiltration volumes. Around half of the respondents reported they take an active role in their treatment. However, respondents were largely unable to relate signs and symptoms to fluid management practice and a third said they would not report common signs and symptoms to clinicians. A fifth of patients reported not to know how ultrafiltration volumes were calculated. Patients responded positively to questions relating to healthcare staff, though with significant variation between units, highlighting differences in perception of care. CONCLUSIONS: Despite a lack of formal acknowledgement in fluid management protocols, patients have significant involvement in decisions regarding fluid removal during dialysis. Furthermore, substantial gaps remain in patient knowledge and engagement. Formalizing the role of patients in these decisions, including patient education, may improve prescription and achievement of target weights.