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/ ).

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.

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.

The time of onset of intradialytic hypotension during a hemodialysis session associates with clinical parameters and mortality.

Intradialytic hypotension (IDH) is a common complication of hemodialysis, but there is no data about the time of onset during treatment. Here we describe the incidence of IDH throughout hemodialysis and associations of time of hypotension with clinical parameters and survival by analyzing data from 21 dialysis clinics in the United States to include 785682 treatments from 4348 patients. IDH was defined as a systolic blood pressure of 90 mmHg or under while IDH incidence was calculated in 30-minute intervals throughout the hemodialysis session. Associations of time of IDH with clinical and treatment parameters were explored using logistic regression and with survival using Cox-regression. Sensitivity analysis considered further IDH definitions. IDH occurred in 12% of sessions at a median time interval of 120-149 minutes. There was no notable change in IDH incidence across hemodialysis intervals (range: 2.6-3.2 episodes per 100 session-intervals). Relative blood volume and ultrafiltration volume did not notably associate with IDH in the first 90 minutes but did thereafter. Associations between central venous but not arterial oxygen saturation and IDH were present throughout hemodialysis. Patients prone to IDH early as compared to late in a session had worse survival. Sensitivity analyses suggested IDH definition affects time of onset but other analyses were comparable. Thus, our study highlights the incidence of IDH during the early part of hemodialysis which, when compared to later episodes, associates with clinical parameters and mortality.

An improved method to estimate absolute blood volume based on dialysate dilution.

Online hemodiafiltration machines equipped with a blood volume monitor and the possibility to rapidly infuse exact amounts of ultrapure dialysate into the extracorporeal circulation can be used to determine absolute blood volume in clinical practice. The aim of the present study was to evaluate the reproducibility of such measurements. Intra-individual reproducibility was evaluated in four measurements taken in hourly intervals within the same dialysis treatment. Ten patients were studied. Absolute blood volumes measured at the beginning and after 1 hour of dialysis were significantly different (80.6 ± 14.5 and 63.9 ± 14.3 mL/kg, P < .001) and highly reproducible between the last three measurements (63.9 ± 14.3, 61.4 ± 13.8, and 60.9 ± 13.9 mL/kg, P = n.s.). Measurement of absolute blood volume after 1 hour of treatment is more precise than earlier measurements and might be better suited for guidance of ultrafiltration.

Assessing the impact of inadequate hydration on isotope-GFR measurement.

Guidelines state that patients undergoing isotope glomerular filtration rate (GFR) tests should maintain adequate hydration, but pragmatically these tests can coincide with procedures requiring the patient not to eat or drink ('nil-by-mouth') for up to 12 hours beforehand. This study investigated the impact of a 12-hour nil-by-mouth regime on GFR measurement. Twelve healthy volunteers were recruited from our institution. Exclusion criteria included diabetes mellitus, being under 18 years of age and pregnancy. Isotope GFR measurements were carried out on these volunteers twice. One of the tests adhered strictly to the British Nuclear Medicine Society (BNMS) guidelines for GFR measurement and the other test was carried out after the volunteers had refrained from eating or drinking anything for 12 hours. The order of these tests was randomly assigned. The results show that after a nil-by-mouth regime, participants' average absolute GFR fell from 108 ml/min to 97 ml/min (p < .01), while normalised GFR fell from 97 ml/min/1.73 m2 to 88 ml/min/1.73m2 (p < .01). Serum creatinine rose from 68 mmol/L to 73 mmol/L (p < .05). There were no changes in blood pressure, serum hydration markers or bio-impedance measured fluid status. Urine analysis showed statistically significant increases in urea, creatinine and osmolality levels after the nil-by-mouth regime. The results highlight the importance of following current guidelines recommending fluid intake during the procedure. Practitioners should consider what other outpatient appointments are being scheduled concurrently with a GFR test.

Cost-effectiveness of bioimpedance-guided fluid management in patients undergoing haemodialysis: the BISTRO RCT.

Background: The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. Objectives: To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Design: Within-trial economic evaluation (cost-utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Setting: Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Participants: Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. Intervention: The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. Main outcome measures: The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. Results: The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI -£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI -0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. Limitations: The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Conclusions: Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work: Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. Funding details: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142).

'Bioimpedance' is a measure of how difficult it is for an electric current to pass through a biological object. Bioimpedance is used in devices that assess fluid status (over- or under-hydration) because it is very sensitive to the amount of water in tissue. Bioimpedance can be used in addition to clinical judgement when deciding how much water should be removed from someone with kidney failure during a dialysis treatment session. This is the first study to examine whether using this treatment represents a cost-effective use of National Health Service resources. We carried out an economic evaluation within a large randomised controlled trial in patients with kidney disease undergoing haemodialysis. We calculated the additional costs and quality-adjusted life-years (a measure that combines quality and quantity of life) using established methods. Over 2 years, our study showed that taking into account bioimpedance measurements about target weight resulted in slightly lower costs and marginally more quality-adjusted life-years, although there is uncertainty around these findings.

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.

Time to Reconsider the Role of Relative Blood Volume Monitoring for Fluid Management in Hemodialysis.

Relative blood volume (RBV) monitoring during hemodialysis has been used to help guide fluid management for decades, although with little supporting evidence. The technique relies on the assumption that variation in RBV during fluid removal reflects the capacity for vascular refilling and that efficient refilling is related to fluid overload. This study investigated the relationship between RBV variation and bioimpedance-based fluid overload in 47 patients on stable hemodialysis. Mean treatment ultrafiltration volume (UFV) was 1.7 L and RBV reduction was 3.2%/hour. Relative blood volume slopes were grouped based on trajectory: flatline (no decrease), linear decrease, or linear decrease followed by flatline. Fluid overload was similar (p > 0.05) across groups pre-dialysis (1.0, 2.2, and 1.6 L, respectively) and post-dialysis (-0.8, -0.1, and -0.1 L), whereas UFV was higher in patients with a linear decrease (1.8, 2.5, and 1.6 L; p = 0.02). Specific ultrafiltration rate, but not fluid overload, was associated with RBV change over dialysis. At least half the patients in each group finished dialysis fluid depleted based on bioimpedance, suggesting that the link between refilling and fluid overload is not as straightforward as previously assumed. These results question the assumptions that the absence of an appreciable decrease in RBV indicates fluid overload, and a rapid fall suggests fluid depletion.

Use of the Body Composition Monitor for Fluid Status Measurements in Elderly Malnourished Subjects.

Most hemodialysis (HD) patients are able to finish dialysis at or below the normally hydrated weight determined using the body composition monitor (BCM). However, a minority become symptomatic when they are still fluid overloaded based on BCM-measured overhydration (OH). Malnourished patients frequently fall into this group, suggesting that they may have OH that is inaccessible to ultrafiltration. To isolate any effect of malnutrition on BCM-measured OH from those relating to renal failure, OH measurements for 20 elderly subjects with normal renal function who were classified as malnourished were compared with an age-matched cohort with no known nutritional issues. Body composition monitor measurements were also made on five malnourished HD patients. Mean OH for malnourished subjects with normal renal function was not significantly different from an age-matched cohort without known nutritional deficiencies (1.3 and 1.1 L, respectively; p = 0.5). Post-dialysis OH for HD patients ranged from -0.1 to +4.5 L. A slightly elevated BCM-measured OH appears to be common in elderly subjects and may be explained by changes in the composition of adipose tissue. The effect of malnutrition could not be isolated from sarcopenia, but this study supports the need for caution when reducing target weight in vulnerable patients.

Use of hand-to-hand measurements for body composition monitoring in patients with inaccessible or amputated feet.

BACKGROUND: The body composition monitor (BCM) provides an objective assessment of fluid status, which has been shown to improve outcomes in patients undergoing haemodialysis. The models used by the BCM were developed and validated using standard wrist-to-ankle bioimpedance measurements, made between electrodes on the hand and foot. However, in patients with inaccessible or amputated feet it is not possible to use standard electrode configurations. OBJECTIVE: To compare hydration measurements made with 'hand-to-hand' (H-H) and 'hand-to-foot' (H-F) electrode configurations in patients with accessible feet or no amputations. METHODS: One hundred and one consecutive patients referred for a BCM measurement were recruited to have H-H measurements at the same time as the usual H-F measurement using the same height and weight. Patients with obvious localised oedema were excluded. RESULTS: Compared with H-F, H-H measurements showed a bias of -0.1 L. For 61% of patients the difference between the readings was within 0.5 L; for 81% it was within 1.0 L. CONCLUSION: The agreement between H-H and H-F measurements was close enough to encourage us to use H-H measurements in patients with inaccessible or amputated feet. Prior to amputation, height and weight are recorded. Target weight (TW) reductions are made gradually when close to normal hydration. Clinically, changes based on H-H measurements appear to be as appropriate as those using H-F. The desired hydration at TW can be established and then TW adjusted to maintain this hydration as the flesh weight fluctuates.

Technology innovation for patients with kidney disease.

The loss of kidney function is a life-changing event leading to life-long dependence on healthcare. Around 5000 people are diagnosed with kidney failure every year. Historically, technology in renal medicine has been employed for replacement therapies. Recently, a lot of emphasis has been placed on technologies that aid early identification and prevent progression of kidney disease, while at the same time empowering affected individuals to gain control over their chronic illness. There is a shift in diversity of technology development, driven by collaborative innovation initiatives such the National Institute's for Health Research Healthcare Technology Co-operative for Devices for Dignity. This has seen the emergence of the patient as a key figure in designing technologies that are fit for purpose, while business involvement has ensured uptake and sustainability of these developments. An embodiment of this approach is the first successful Small Business Research Initiative in the field of renal medicine in the UK.

Planar parathyroid localization scintigraphy: a comparison of subtraction and 1-, 2- and 3-h washout protocols.

INTRODUCTION: With the advent of minimally invasive surgery to treat hyperparathyroidism, preoperative imaging of parathyroid glands has become routine practice. Scintigraphy and ultrasound are the two most common imaging techniques. Despite this, published sensitivities for scintigraphy vary enormously, and there is a multitude of protocols performed. This investigation compares the accuracies of planar subtraction and multiple washout images in the same group of patients. METHODS: We followed up 190 consecutive patients who underwent a combined subtraction and washout scintigraphy protocol and compared the results against surgical outcomes, taken as the gold standard. Technetium-99m sestamibi images were acquired at 5 min and at 1, 2 and 3 h, followed by a technetium-99m pertechnetate image for subtraction. Sixty-four of these patients also underwent ultrasound imaging for localization. The relative value of each part of the protocol in localizing adenomas was compared. RESULTS: The overall accuracy of this combined protocol for correct localization of both the side and axial level of parathyroid adenomas was 81% (90% when considering the side of the adenoma alone). Of all the nuclear medicine images produced, subtraction was the most useful. The 1 and 2 h washout images were comparable but the 3 h image added no value. The accuracy of ultrasound imaging was 55% for the side and pole and 60% for the side of the adenoma. CONCLUSION: For optimal accuracy a planar parathyroid localization protocol should include subtraction and at least one washout image between 1 and 2 h after injection.