Modulation of the expression of connexins 37, 40, and 43 in endothelial cells in a culture.

Connexin (Cx) 37, 40, and 43 are implicated in vascular function, specifically in the electrical coupling of endothelial cells and vascular smooth-muscle cells. In the present study, we investigated whether factors implicated in vascular dysfunction can modulate the gene expression of Cx37, Cx40, and Cx43 and whether this is associated with changes in endothelial layer barrier function in human microvascular endothelial cells (HMEC-1). First, HMEC-1 were subjected to stimuli for 4 and 8 h. We tested their responses to DETA-NONOate, H2O2, high glucose, and angiotensin II, none of which relevantly affected the transcription of the connexin genes. Next, we tested inflammatory factors IL-6, interferon gamma (IFNγ), and TNFα. IFNγ (10 ng/mL) consistently induced Cx40 expression at 4 and 8 h to 10-20-fold when corrected for the control. TNFα and IL-6 resulted in small but significant depressions of Cx37 expression at 4 h. Two JAK inhibitors, epigallocatechin-3-gallate (EGCG) (100-250 µM) and AG490 (100-250 µM), dose-dependently inhibited the induction of Cx40 expression by IFNγ. Subsequently, HMEC-1 were subjected to 10 ng/mL IFNγ for 60 h, and intercellular and transcellular impedance was monitored by electric cell-substrate impedance sensing (ECIS). In response to IFNγ, junctional-barrier impedance increased more than cellular-barrier impedance; this was prevented by AG490 (5 µM). In conclusion, IFNγ can strongly induce Cx40 expression and modify the barrier properties of the endothelial cell membrane through the JAK/STAT pathway. Moreover, the Cx37, Cx40, and Cx43 expression in endothelial cells is stable and, apart from IFNγ, not affected by a number of factors implicated in endothelial dysfunction and vascular diseases.

Association Between Arterial Stiffness and Measures of Autonomic Dysfunction in People With Chronic Kidney Disease.

Background: Autonomic nervous system (ANS) dysfunction and vascular stiffness increase cardiovascular risk in people with chronic kidney disease (CKD). Chronic elevations in sympathetic activity can lead to increased arterial stiffness; however, the relationship between these variables is unknown in CKD. Objective: To explore the association between measures of autonomic function and arterial stiffness in patients with moderate-to-severe CKD. Methods: This study was a prespecified secondary analysis of a randomized controlled trial. This included the following measures: 24-hour ambulatory blood pressure (BP), carotid-femoral and carotid-radial pulse wave velocity (PWV), and postexercise heart rate recovery (HRR). We used mixed effect linear regression models with Bayesian information criteria (BIC) to assess the contribution of ANS measurements. Results: Forty-four patients were included in the analysis. Mean carotid-femoral and carotid-radial PWV were 7.12 m/s (95% CI 6.13, 8.12) and 8.51 m/s (7.90, 9.11), respectively. Mean systolic dipping, calculated as percentage change in mean systolic readings from day to night, was 10.0% (95% CI 7.79, 12.18). Systolic dipping was independently associated with carotid-radial PWV, MD -0.09 m/s (95% CI -0.15, -0.02) and had the lowest BIC. Conclusions: Systolic dipping was associated with carotid-radial PWV in people with moderate-to-severe CKD; however, there was no association with carotid-femoral PWV. Systolic dipping may be a feasible surrogate of ANS function, as the association with carotid-radial PWV was consistent with the minimal clinically important difference (MCID). Future studies are needed to define the relationship between ANS function, arterial stiffness, and CV events over time in people with CKD.

Contexte: Le dysfonctionnement du système nerveux autonome (SNA) et la rigidité artérielle augmentent le risque d'événements cardiovasculaires chez les personnes atteintes d'insuffisance rénale chronique (IRC). Les élévations chroniques de l'activité sympathique peuvent accroître la rigidité artérielle, mais on ne connaît pas le lien entre ces variables en contexte d'IRC. Objectif: Explorer l'association entre les mesures de la fonction autonome et la rigidité artérielle chez les patients atteints d'IRC modérée ou grave. Méthodologie: Cette étude était l'analyze secondaire prédéfinie d'un essai contrôlé randomisé. Mesures incluses: le suivi de la pression artérielle (PA) ambulatoire sur 24 heures, la vitesse de l'onde de pouls (VOP) carotido-fémorale et carotido-radiale, et la récupération de la fréquence cardiaque (HRR­Heart Rate Recovery) après l'effort. Nous avons eu recours à des modèles de régression linéaire à effets mixtes avec critères d'information bayésiens (BIC ­ Bayesian Information Criteria) pour évaluer la contribution des mesures du SNA. Résultats: Quarante-quatre patients sont inclus dans l'analyze. La valeur moyenne des VOP carotido-fémorale et carotido-radiale était respectivement de 7,12 m/s (IC 95 %: 6,13 à 8,12) et de 8,51 m/s (IC 95 %: 7,90 à 9,11). La chute systolique moyenne, calculée en pourcentage de variation entre les valeurs systoliques moyennes du jour et de la nuit, était de 10,0 % (IC 95 %: 7,79 à 12,18). La chute systolique a été indépendamment associée à la VOP carotido-radiale, avec un écart moyen de -0,09 m/s (IC 95 %: -0,15 à -0,02) et a présenté les plus faibles BIC. Conclusion: La chute systolique a été associée à la VOP carotido-radiale chez les personnes atteintes d'IRC modérée ou grave, mais aucune association n'a été observée avec la VOP carotido-fémorale. La chute systolique pourrait être un substitut de la fonction du SNA, car l'association avec la VOP carotido-radiale était cohérente avec la différence minimale cliniquement importante (DMCI). D'autres études sont nécessaires pour mieux définir la relation entre la fonction du SNA, la rigidité artérielle et les événements cardiovasculaires au fil du temps chez les personnes atteintes d'IRC.

Reduced tubuloglomerular feedback activity and absence of its synchronization in a connexin40 knockout rat.

Introduction: Tubuloglomerular feedback (TGF) is the negative feedback component of renal blood flow (RBF) autoregulation. Neighbouring nephrons often exhibit spontaneous TGF oscillation and synchronization mediated by endothelial communication, largely via connexin40 (Cx40). Methods: We had a knockout (KO) rat made that lacks Cx40. One base pair was altered to create a stop codon in exon 1 of Gja5, the gene that encodes Cx40 (the strain is WKY-Gja55em1Mcwi). Blood pressure (BP)-RBF transfer functions probed RBF dynamics and laser speckle imaging interrogated the dynamics of multiple efferent arterioles that reach the surface (star vessels). Results: The distribution of wild type (WT), heterozygote, and KO pups at weaning approximated the Mendelian ratio of 1:2:1; growth did not differ among the three strains. The KO rats were hypertensive. BP-RBF transfer functions showed low gain of the myogenic mechanism and a smaller TGF resonance peak in KO than in WT rats. Laser speckle imaging showed that myogenic mechanism had higher frequency in KO than in WT rats, but similar maximum spectral power. In contrast, the TGF frequency was similar while peak power of its oscillation was much smaller in KO than in WT rats. In WT rats, plots of instantaneous TGF phase revealed BP-independent TGF synchronization among star vessels. The synchronization could be both prolonged and widespread. In KO rats TGF synchronization was not seen, although BP transients could elicit short-lived TGF entrainment. Discussion: Despite the reduced TGF spectral power in KO rats, there was sufficient TGF gain to induce oscillations and therefore enough gain to be effective locally. We conclude that failure to synchronize is dependent, at least in part, on impaired conducted vasomotor responses.

Bioimpedance-Guided Monitoring of Volume Status in Patients With Kidney Disease: A Systematic Review and Meta-Analysis.

Background and Objective: Bioimpedance technologies are increasingly used to determine fluid status in patients with chronic kidney disease and those with end-stage kidney disease on dialysis. We aimed to determine whether this technology improves clinical outcomes as compared with usual care. Methods: We performed a systematic review and meta-analysis of trials, comparing fluid management guided by bioimpedance technologies to standard of care in patients with chronic kidney disease. Our primary outcome was all-cause mortality. Secondary outcomes included blood pressure control, all-cause hospitalization, major adverse cardiovascular events, and change in left ventricular mass index. Results: Our search identified 819 citations of which 12 randomized controlled trials were included (2420 patients). No studies of non-dialysis-dependent chronic kidney disease patients met inclusion criteria. Mean age was 55 years and mean follow-up was 1 year. There was a statistically significant difference in all-cause mortality between both arms studied (risk ratio [RR] 0.64, 95% confidence interval [CI]: 0.44, 0.99). Better blood pressure control was observed in the bioimpedance arm of the included articles, weighted mean differences (WMD) -3.13 mm Hg (95% CI: -5.73, -0.53 mm Hg) for systolic blood pressure and WMD -2.50 mm Hg (95% CI: -4.36, -0.64 mm Hg) for diastolic blood pressure. No difference was observed concerning the other outcomes. Conclusions: Among patients on maintenance dialysis, bioimpedance-guided volume management showed decreased all-cause mortality and blood pressure but no significant difference in all-cause hospitalization, major adverse cardiac event, or change in left ventricular mass index. This may be due to a younger population sample than previous articles. Moreover, our study identified a knowledge gap by highlighting the lack of studies evaluating this technology in non-dialysis-dependent chronic kidney disease patients.

Contexte et objectif: Les technologies de bio-impédance sont de plus en plus utilisées pour déterminer le statut hydrique des patients atteints d'insuffisance rénale chronique et des patients atteints d'insuffisance rénale terminale sous dialyze. Notre objectif était de vérifier si cette technologie améliore les résultats cliniques des patients par rapport aux soins habituels. Méthodologie: Nous avons procédé à une revue systématique et à une méta-analyze d'essais comparant la gestion des fluides guidée par les technologies de bio-impédance aux normes de soins chez les patients atteints d'insuffisance rénale chronique. Le principal critère de jugement était la mortalité toutes causes confondues. La régulation de la pression artérielle, l'hospitalization toutes causes confondues, les événements cardiovasculaires majeurs indésirables et la modification de l'index de masse ventriculaire gauche constituaient les critères de jugement secondaires. Résultats: Notre recherche a permis de répertorier 819 citations, desquelles 12 essais contrôlés randomisés ont été retenus (2 420 patients). Aucune étude portant sur des patients atteints d'insuffisance rénale chronique non dépendants de la dialyze ne remplissait les critères d'inclusion. L'âge moyen des sujets était de 55 ans et le suivi moyen était d'un an. Une différence statistiquement significative a été observée entre les deux bras étudiés en ce qui concerne la mortalité toutes causes confondues (RR: 0.64; IC 95% entre: 0.44, 0.99). Une meilleure régulation de la pression artérielle a été observée dans le bras de bio-impédance des manuscrits inclus, soit une moyenne pondérée des écarts de −3.13 mm Hg (IC 95% entre: −5.73, −0.53 mm Hg) pour la pression artérielle systolique et de −2.50 mm Hg (IC 95% entre: −4.36, −0.64 mm Hg) pour la pression artérielle diastolique. Aucune différence n'a été observée pour les autres résultats. Conclusion: Chez les patients sous dialyze d'entretien, la prise en charge du volume guidée par la bio-impédance a montré une diminution de la mortalité toutes causes confondues et une meilleure régulation de la pression artérielle. Aucune différence significative n'a été cependant observée dans les hospitalisations toutes causes confondues, les événements cardiaques majeurs indésirables ou la modification de l'index de masse ventriculaire gauche. Ce résultat pourrait être attribuable au fait que l'échantillon de population était cette fois-ci plus jeune que les populations étudiées dans les manuscrits précédents. De plus, notre étude a permis d'identifier un écart dans les connaissances en soulignant le manque d'études évaluant cette technologie chez les patients atteints d'insuffisance rénale chronique non dépendants de la dialyze.

Ex vivo hemolysis: Three cases demonstrating mechanically-induced hemolysis from the extracorporeal circuit during hemodialysis.

Sporadic mechanically-induced hemolysis associated with kinks in extracorporeal blood circuits during hemodialysis is a rare but potentially serious complication that exhibits laboratory features consistent with both in vivo and in vitro hemolysis. Misclassification of clinically significant hemolysis as in vitro can lead to inappropriate test cancellation and delayed medical interventions. Here, we report three cases of hemolysis attributed to kinked hemodialysis blood lines, which we have defined as "ex vivo" hemolysis. All three cases demonstrated an initial mixed picture of laboratory features consistent with both classifications of hemolysis. Specifically, absent features of in vivo hemolysis on blood film smear despite normal potassium led to the misclassification of these samples as in vitro hemolysis and their cancellation. A proposed mechanism for these overlapping laboratory features is the recirculation of damaged red blood cells from the kinked or pinched hemodialysis line back into the patient circulation producing an "ex vivo" hemolysis presentation. In two of the three cases, the patients developed acute pancreatitis as a result of hemolysis and required urgent medical follow up. We developed a decision pathway to help laboratories in identifying and handling these samples by recognizing that in vitro and in vivo hemolysis have overlapping laboratory features. These cases highlight the need for laboratorians and the clinical care team to be vigilant about mechanically-induced hemolysis from the extracorporeal circuit during hemodialysis. Communication is critical to identify the cause of hemolysis in these patients and prevent unnecessary delays in result reporting.

Characterizing Hypertension Specialist Care in Canada: A National Survey.

Background: The hypertension specialist often receives referrals of patients with young-onset, severe, difficult-to-control hypertension, patients with hypertensive emergencies, and patients with secondary causes of hypertension. Specialist hypertension care compliments primary care for these complex patients and contributes to an overall hypertension control strategy. The objective of this study was to characterize hypertension centres and the practice patterns of Canadian hypertension specialists. Methods: Adult hypertension specialists across Canada were surveyed to describe hypertension centres and specialist practice in Canada, including the following: the patient population managed by hypertension specialists; details on how care is provided; practice pattern variations; and differences in access to specialized hypertension resources across the country. Results: The survey response rate was 73.5% from 25 hypertension centres. Most respondents were nephrologists and general internal medicine specialists. Hypertension centres saw between 50 and 2500 patients yearly. A mean of 17% (± 15%) of patients were referred from the emergency department and a mean of 52% (± 24%) were referred from primary care. Most centres had access to specialized testing (adrenal vein sampling, level 1 sleep studies, autonomic testing) and advanced therapies for resistant hypertension (renal denervation). Considerable heterogeneity was present in the target blood pressure in young people with low cardiovascular risk and in the diagnostic algorithms for investigating secondary causes of hypertension. Conclusions: These results summarize the current state of hypertension specialist care and highlight opportunities for further collaboration among hypertension specialists, including standardization of the approach to specialist care for patients with hypertension.

Contexte: Le spécialiste de l'hypertension reçoit souvent des patients orientés pour une hypertension sévère, d'apparition précoce et difficile à maîtriser, pour une urgence hypertensive ou pour des causes secondaires de l'hypertension. Les soins spécialisés de l'hypertension complètent les soins primaires pour ces cas complexes et font partie d'une stratégie globale de maîtrise de l'hypertension. Cette étude avait pour objectif de caractériser les centres de traitement de l'hypertension et les habitudes de pratique des spécialistes canadiens qui traitent l'hypertension. Méthodologie: Un sondage a été mené auprès de spécialistes de l'hypertension adulte de l'ensemble du Canada afin de décrire les centres de traitement de l'hypertension et la pratique des spécialistes au Canada, notamment les éléments suivants : la population de patients prise en charge par des spécialistes de l'hypertension, les renseignements sur la façon dont les soins sont prodigués, les variations dans les habitudes de pratique ainsi que les différences relatives à l'accès aux ressources spécialisées en hypertension à l'échelle du pays. Résultats: Le taux de réponse au sondage a été de 73,5 % dans 25 centres de l'hypertension. La plupart des répondants étaient des néphrologues et des spécialistes en médecine interne générale. Les centres de l'hypertension recevaient entre 50 et 2500 patients par année. En moyenne, 17 % (± 15 %) des patients provenaient du service des urgences et 52 % (± 24 %) provenaient d'une unité de soins primaires. La plupart des centres avaient accès à des tests spécialisés (prélèvements veineux surrénaliens, études du sommeil de niveau 1, tests autonomes) et à des traitements avancés pour l'hypertension résistante (dénervation rénale). Une hétérogénéité considérable a été constatée en ce qui concerne la pression artérielle cible chez les jeunes présentant un faible risque cardiovasculaire et les algorithmes diagnostiques pour étudier les causes secondaires de l'hypertension. Conclusions: Ces résultats résument la situation actuelle des soins spécialisés de l'hypertension et font ressortir des occasions d'accroître la collaboration entre les spécialistes de l'hypertension, notamment en ce qui concerne une normalisation de l'approche des soins spécialisés pour les patients hypertendus.

Changes in Proximal Tubular Reabsorption Modulate Microvascular Regulation via the TGF System.

This review paper considers the consequences of modulating tubular reabsorption proximal to the macula densa by sodium-glucose co-transporter 2 (SGLT2) inhibitors, acetazolamide, and furosemide in states of glomerular hyperfiltration. SGLT2 inhibitors improve renal function in early and advanced diabetic nephropathy by decreasing the glomerular filtration rate (GFR), presumably by activating the tubuloglomerular feedback (TGF) mechanism. Central in this paper is that the renoprotective effects of SGLT2 inhibitors in diabetic nephropathy can only be partially explained by TGF activation, and there are alternative explanations. The sustained activation of TGF leans on two prerequisites: no or only partial adaptation should occur in reabsorption proximal to macula densa, and no or only partial adaptation should occur in the TGF response. The main proximal tubular and loop of Henle sodium transporters are sodium-hydrogen exchanger 3 (NHE3), SGLT2, and the Na-K-2Cl co-transporter (NKCC2). SGLT2 inhibitors, acetazolamide, and furosemide are the most important compounds; inhibiting these transporters would decrease sodium reabsorption upstream of the macula densa and increase TGF activity. This could directly or indirectly affect TGF responsiveness, which could oppose sustained TGF activation. Only SGLT2 inhibitors can sustainably activate the TGF as there is only partial compensation in tubular reabsorption and TGF response. SGLT2 inhibitors have been shown to preserve GFR in both early and advanced diabetic nephropathy. Other than for early diabetic nephropathy, a solid physiological basis for these effects in advanced nephropathy is lacking. In addition, TGF has hardly been studied in humans, and therefore this role of TGF remains elusive. This review also considers alternative explanations for the renoprotective effects of SGLT2 inhibitors in diabetic patients such as the enhancement of microvascular network function. Furthermore, combination use of SGLT2 inhibitors and angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs). in diabetes can decrease inflammatory pathways, improve renal oxygenation, and delay the progression of diabetic nephropathy.

Impact of Home Telemonitoring and Management Support on Blood Pressure Control in Nondialysis CKD: A Systematic Review and Meta-Analysis.

Background: Hypertension is a major cause of cardiovascular disease, chronic kidney disease (CKD), and death. Several studies have demonstrated the efficacy of home blood pressure telemonitoring (HBPT) for blood pressure (BP) control and outcomes, but the effects of this intervention remain unclear in patients with CKD. Objective: To determine the impact of HBPT on cardiovascular-related and kidney disease-related outcomes in patients with CKD. Design: Systematic review and meta-analysis. Setting: All studies that met our criteria regardless of country of origin. Participants: Patients with chronic kidney disease included in studies using HBPT for BP assessment and control. Measurements: Descriptive and quantitative analysis of our primary and secondary outcomes. Methods: We searched MEDLINE, Embase, CINAHL Plus, PsycINFO, Cochrane CENTRAL, Web of Science, and gray literature from inception for observational and randomized controlled studies in nondialysis (ND) CKD using HBPT for BP control. We selected studies that used HBPT as intervention (with or without a control arm) for BP control in ND-CKD populations. The primary outcome was change in mean systolic BP (SBP) and mean diastolic BP (DBP). Results: We selected 7 studies from 1669 articles that were initially identified. Overall, pooled estimates in the mean difference (MD) for SBP and DBP were -8.8 mm Hg; 95% confidence interval (CI): -16.2 to -1.4; P = .02 and -2.4 mm Hg; 95% CI: -3.8 to -1.0; P < .001, respectively. For studies comparing intervention with usual care (UC), pooled estimate in MD for SBP was -8.0 mm Hg (P = .02) with no significant reduction for DBP (-2.6 mm Hg; P = .18). In studies without a UC arm, both SBP and DBP were not significantly reduced (P > .05). The pooled estimate in MD for estimated glomerular filtration rate showed a significant improvement (5.4 mL/min/1.73 m2; P < .001). Limitations: Heterogeneity and few available studies for inclusion limited our ability to identify a robust link between HBPT use and BP and kidney function improvement. Conclusion: Home blood pressure telemonitoring is associated with mild lowering of BP and moderately improved kidney function in patients with CKD. However, larger studies with improved designs and prolonged interventions are still needed to assess the effects of HBPT on patients' outcomes. PROSPERO registration ID: CRD42020190705.

Contexte: L'hypertension est une cause majeure de maladie cardiovasculaire, d'insuffisance rénale chronique (IRC) et de mortalité. Plusieurs études ont montré l'efficacité de la télésurveillance de la pression artérielle à domicile (TSPA) pour le contrôle de la pression artérielle (PA) et les évènements cliniques, mais les effets de cette intervention demeurent mal connus chez les patients atteints d'IRC. Objectif: Évaluer l'effet de la TSPA sur les évènements cardiovasculaires et rénaux chez les patients atteints d'IRC. Conception: Revue systématique et méta-analyse. Sources: Toutes les études satisfaisant nos critères, peu importe le pays d'origine. Sujets: Les patients atteints d'IRC inclus dans les études portant sur l'utilisation de la TSPA pour réguler la pression artérielle. Mesures: Analyse descriptive et quantitative de nos résultats primaires et secondaires. Méthodologie: Nous avons consulté les bases de données MEDLINE, embase, CINAHL plus, PsycINFO, Cochrane CENTRAL et Web of Science, de même que la littérature grise depuis leur début, à la recherche des études observationnelles contrôlées et randomisées portant sur l'utilisation de la TSPA pour contrôler la PA chez des patients atteints d'IRC non dialysés. Nous avons sélectionné les études (avec ou sans bras témoin) utilisant l'intervention (TSPA pour contrôler la PA) dans des populations de patients atteints d'IRC non dialysés. Le principal critère d'évaluation était un changement de la pression systolique moyenne (PSM) et de la pression diastolique moyenne (PDM). Résultats: Nous avons retenu sept études parmi les 1 669 articles initialement répertoriés. Dans l'ensemble, les estimations regroupées de la différence moyenne (DM) pour la PSM et la PDM étaient de −8,8 mmHg (IC 95%: −16,2 à −1,4; P = 0,02) et de −2,4 mmHg (IC 95%: −3,8 à −1,0; P < 0,001) respectivement. Dans les études qui comparaient l'intervention aux soins habituels (SH), les estimations regroupées de la DM s'établissaient à −8,0 mmHg (P = 0,02) pour la PSM, sans réduction significative pour la PDM (−2,6 mmHg; P = 0,18). Dans les études sans bras SH, aucune réduction significative n'a été observée pour la PSM et la PDM (P > 0,05). L'estimation groupée de la DM pour le débit de filtration glomérulaire estimé (DFGe) a montré une amélioration significative (5,4 ml/min/1,73 m2; P < 0,001). Limites: Le peu d'études disponibles pour inclusion et leur hétérogénéité limitent notre capacité à établir un lien robuste entre l'utilisation de la TSPA et une amélioration de la PA et de la fonction rénale. Conclusion: La TSPA est associée à une légère baisse de la PA et à une amélioration modérée de la fonction rénale chez les patients atteints d'IRC. Des études de plus grande envergure, avec des conceptions améliorées et des interventions prolongées, sont nécessaires pour mieux évaluer les effets de la TSPA sur les résultats des patients.

The impact of community-based non-pharmacological interventions on cardiovascular and kidney disease outcomes in remote dwelling Indigenous communities: A scoping review protocol.

INTRODUCTION: Indigenous people represent approximately 5% of the world's population. However, they often have a disproportionately higher burden of cardiovascular disease (CVD) risk and chronic kidney disease (CKD) than their equivalent general population. Several non-pharmacological interventions (e.g., educational) have been used to reduce CVD and kidney disease risk factors in Indigenous groups. The aim of this paper is to describe the protocol for a scoping review that will assess the impact of non-pharmacological interventions carried out in Indigenous and remote dwelling populations to reduce CVD risk factors and CKD. MATERIALS AND METHODS: This scoping review will be guided by the methodological framework for conducting scoping studies developed by Arksey and O'Malley. Both empirical (Medline, Embase, Cochrane Library, CINAHL, ISI Web of Science and PsycINFO) and grey literature references will be assessed if they focused on interventions targeted at reducing CVD or CKD among Indigenous groups. Two reviewers will independently screen references in consecutive stages of title/abstract screening and then full-text screening. Impact of interventions used will be assessed using the reach, effectiveness, adoption, implementation, maintenance (RE-AIM) framework. A descriptive overview, tabular summaries, and content analysis will be carried out on the extracted data. ETHICS AND DISSEMINATION: This review will collect and analyse evidence on the impact of interventions of research carried out to reduce CVD and CKD among Indigenous populations. Such evidence will be disseminated using traditional approaches that includes open-access peer-reviewed publication, scientific presentations, and a report. Also, we will disseminate our findings to the government and Indigenous leaders. Ethical approval will not be required for this scoping review as the data used will be extracted from already published studies with publicly accessible data.

Impact of quality improvement initiatives to improve CKD referral patterns: a systematic review protocol.

INTRODUCTION: Chronic kidney disease (CKD) is a global-health problem. A significant proportion of referrals to nephrologists for CKD management are early and guideline-discordant, which may lead to an excess number of referrals and increased wait-times. Various initiatives have been tested to increase the proportion of guideline-concordant referrals and decrease wait times. This paper describes the protocol for a systematic review to study the impacts of quality improvement initiatives aimed at decreasing the number of non-guideline concordant referrals, increasing the number of guideline-concordant referrals and decreasing wait times for patients to access a nephrologist. METHODS AND ANALYSIS: We developed this protocol by using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (2015). We will search the following empirical electronic databases: MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science, PsycINFO and grey literature for studies designed to improve guideline-concordant referrals or to reduce unnecessary referrals of patients with CKD from primary care to nephrology. Our search will include all studies published from database inception to April 2021 with no language restrictions. The studies will be limited to referrals for adult patients to nephrologists. Referrals of patients with CKD from non-nephrology specialists (eg, general internal medicine) will be excluded. ETHICS AND DISSEMINATION: Ethics approval will not be required, as we will analyse data from studies that have already been published and are publicly accessible. We will share our findings using traditional approaches, including scientific presentations, open access peer-reviewed platforms, and appropriate government and public health agencies. PROSPERO REGISTRATION NUMBER: CRD42021247756.

Chronic, Combined Cardiac and Renal Dysfunction Exacerbates Renal Venous Pressure-Induced Suppression of Renal Function in Rats.

BACKGROUND AND OBJECTIVE: Increased renal venous pressure (RVP) is common in combined heart and kidney failure. We previously showed that acute RVP elevation depresses renal blood flow (RBF), glomerular filtration rate (GFR), and induces renal vasoconstriction in the absence of changes in blood pressure in healthy rats. We used our established rodent model of chronic combined heart and kidney failure (H/KF) to test whether RVP elevation would impair cardiovascular stability, renal perfusion and exacerbate renal dysfunction. METHODS: Male rats were subjected to 5/6 nephrectomy (SNx or Sham) and 6% high salt diet followed 7 weeks later by ligation of the left anterior descending coronary artery (CL or Sham). Experimental groups: CL + SNx (n = 12), Sham CL + SNx (n = 9), CL+ Sham SNx (n = 6), and Sham Control (n = 6). Six weeks later, anesthetized rats were subjected to an acute experiment whereupon mean arterial pressure (MAP), heart rate (HR), RVP, RBF, and GFR were measured at baseline and during elevation of RVP to 20-25 mmHg for 120 min. RESULTS: Baseline MAP, HR, RBF, and renal vascular conductance (RVC) were comparable among groups. Baseline GFR was significantly depressed in CL + SNx and Sham CL + SNx groups compared to Sham Control and CL + Sham SNx groups. Upon RVP increase, MAP and HR fell in all groups. Increased RVP exacerbated the reduction in RBF in CL + SNx (-6.4 ± 0.9 ml/min) compared to Sham Control (-3.7 ± 0.9 ml/min, p < 0.05) with intermediate responses in Sham CL + SNx (-6.8 ± 1.3 ml/min) and CL + Sham SNx (-5.1 ± 0.4 ml/min) groups. RVP increase virtually eliminated GFR in CL + SNx (-99 ± 1%), Sham CL + SNx (-95 ± 5%), and CL + Sham SNx (-100%) groups compared to Sham Control (-84 ± 15% from baseline; p < 0.05). Renal vascular conductance dropped significantly upon RVP increase in rats with HF (CL + SNx: -0.035 ± 0.011; CL + Sham SNx: -0.050 ± 0.005 ml/min·mmHg-1, p < 0.05) but not Sham CL + SNx (-0.001 ± 0.019 ml/min·mmHg-1) or Control (-0.033 ± mL/min·mmHg-1). CONCLUSION: Chronic combined heart and kidney failure primarily impairs renal hemodynamic stability in response to elevated RVP compared to healthy rats.

Telemonitoring and Case Management for Hypertensive and Remote-Dwelling Patients With Chronic Kidney Disease-The Telemonitoring for Improved Kidney Outcomes Study (TIKO): A Clinical Research Protocol.

BACKGROUND: Hypertension, together with poorly controlled blood pressure (BP) are known risk factors for kidney disease and progression to kidney failure as well as increased cardiovascular (CV) morbidity and mortality. Several studies in patients without kidney disease have demonstrated the efficacy of home BP telemonitoring (HBPT) for BP control. OBJECTIVE: The primary aim of this study is to assess the mean difference in systolic BP (SBP) at 12 months, from baseline in remote dwelling patients with hypertension and chronic kidney disease (CKD) in Northern Alberta, Canada, comparing HBPT + usual care versus HBPT + a case manager. Other secondary objectives, including cost-effectiveness and acceptability of HBPT as well as occurrence of adverse events will also be assessed. DESIGN: This study is designed as a pragmatic randomized controlled trial (RCT) of HBPT plus clinical case management compared to HBPT with usual care. SETTING: Peace River region in Northern Alberta Region, Canada. PATIENTS: Primary care patients with CKD and hypertension. MEASUREMENTS: Eligible patients will be randomized 1:1 to HBPT + BP case management versus HBPT + usual care. In the intervention arm, BP will be measured 4 times daily for 1 week, with medications titrated up or down by the study case manager until guideline targets (systolic BP [SBP]: <130 mmHg) are achieved. Once BP is controlled, (ie, to guideline-concordant targets), this 1-week protocol will be repeated every 3 months for 1 year. Patients in the control arm will also follow the same BP measurement protocol; however, there will be no interactions with the case manager; they will share their BP readings with their primary care physicians or nurse practitioners at scheduled visits. LIMITATIONS: Potential limitations of this study include the relatively short duration of follow-up, possible technological pitfalls, and need for patients to own a smartphone and have access to the internet to participate. CONCLUSIONS: As this study will focus on a high-risk population that has been characterized by a large care gap, it will generate important evidence that would allow targeted and effective population-level strategies to be implemented to improve health outcomes for high-risk hypertensive CKD patients in Canada's remote communities. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT number: NCT04098354).

CONTEXTE: L'hypertension et la pression artérielle (PA) mal contrôlée sont des facteurs de risque reconnus pour la néphropathie et la progression vers l'insuffisance rénale, en plus de poser un risque accru de morbidité et de mortalité cardiovasculaires. Plusieurs études chez des patients sans néphropathie ont démontré l'efficacité de la télésurveillance de la PA à domicile (TSPA) pour le contrôle de la PA. OBJECTIFS: Le principal objectif est d'évaluer la différence moyenne de pression artérielle systolique (PAS) après 12 mois par rapport à sa valeur initiale chez des patients atteints d'hypertension et d'insuffisance rénale chronique (IRC) habitant les communautés éloignées du nord de l'Alberta (Canada). Cet objectif sera atteint en comparant la TSPA + soins habituels à la TSPA + gestionnaire de cas. D'autres objectifs secondaires, notamment le rapport coût/efficacité de la TSPA, son acceptation et la survenue d'événements indésirables seront également évalués. TYPE D'ÉTUDE: Cette étude est conçue comme un essai randomisé contrôlé (ERC) pragmatique comparant la TSPA + prise en charge clinique des cas à la TSPA + soins habituels. CADRE: Région de Peace River dans le nord de l'Alberta (Canada). SUJETS: Patients atteints d'IRC et d'hypertension recevant des soins de santé primaires. MESURES: Les patients admissibles seront répartis 1:1 dans le groupe TSPA + prise en charge du cas d'hypertension ou dans le groupe témoin (TSPA + soins habituels). Dans le groupe d'intervention, la PA sera mesurée quatre fois par jour pendant une semaine, avec augmentation ou réduction de la médication par le gestionnaire de cas de l'étude jusqu'à ce que la cible de référence (PAS : <130 mmHg) soit atteinte. Une fois la PA contrôlée (c.-à-d. conforme aux cibles recommandées), ce protocole sur une semaine sera répété tous les trois mois pendant un an. Les patients du groupe témoin suivront le même protocole de mesure de la PA, mais sans interactions avec le gestionnaire de cas, ils transmettront plutôt leurs mesures de PA à leur médecin de soins primaires ou aux infirmières praticiennes lors de visites prévues. LIMITES: Cette étude est notamment limitée par la durée relativement courte du suivi, de possibles difficultés technologiques et la nécessité pour les participants de posséder un téléphone intelligent et d'avoir accès à l'Internet. CONCLUSION: Puisque cette étude se penchera sur une population à risque élevé et marquée par d'importantes lacunes en matière de soins, elle générera des données importantes qui aideront à mettre en œuvre des stratégies ciblées et efficaces au niveau de la population afin d'améliorer les évènements cliniques des patients hypertendus et atteints d'IRC à haut risque habitant les communautés éloignées au Canada.

Designing an App for Immunosuppression Adherence and Communication: A Qualitative Approach.

BACKGROUND: Immunosuppression nonadherence may be the most important factor limiting long-term allograft survival. OBJECTIVE: Following user-centered design, we explored the essential priorities and preferences of kidney transplant recipients and healthcare providers (HCP) to inform development of a smartphone app to improve immunosuppression adherence and communication. DESIGN: A qualitative descriptive research design was used. SETTING: The University of Alberta Hospital adult kidney transplant program in Edmonton, Canada. PARTICIPANTS: Participants were recruited by convenience sampling and included 32 kidney transplant recipients and 11 HCPs. METHODS: Seven focus groups (5 with recipients and 2 with HCPs) were conducted to inform app development. Sessions were recorded, and transcripts were coded to elucidate themes. RESULTS: App development to improve adherence was not a priority for HCP. Recipients prioritized choice: that all features be optional. Recipients preferred support while traveling; access to laboratory results; and use by younger or newly transplanted recipients. Both recipients and HCP preferred linkage to pharmacy; and self-management and accountability.For the app to improve communication, HCPs believed the priorities to be addressed included: clarity on scope of app; legal, ethical, and professional obligations; and charting. Both recipients and HCP prioritized HCP workload, and broader medication and health concerns. Healthcare providers preferred tech support; both recipients and HCPs preferred app access for nontransplant HCP. LIMITATIONS: Limitations include underrepresentation of physicians, recipients with racial/ethnic diversity, and potential selection bias of transplant recipients who perceived themselves to be adhering to immunosuppression medications. CONCLUSION: Future research is needed for the app to become a comprehensive, secure platform for broader communication between recipients and HCP, pharmacies, and nontransplant clinicians while streamlining HCP workload.

CONTEXTE: La non-observance du traitement immunosuppresseur pourrait s'avérer le facteur limitant ayant la plus grande incidence sur la survie à long terme de l'allogreffe. OBJECTIFS: Suivant une conception centrée sur l'utilisateur, nous avons exploré les préférences et les priorités essentielles des receveurs d'une greffe rénale et des fournisseurs de soins de santé (FSS) afin d'orienter le développement d'une application pour téléphones intelligents visant à améliorer les communications et l'observance du traitement immunosuppresseur. TYPE D'ÉTUDE: Un plan de recherche qualitatif et descriptif a été utilisé. CADRE: Le program de transplantation rénale pour adultes du University of Alberta Hospital à Edmonton (Canada). PARTICIPANTS: Les participants ont été recrutés par échantillonnage de commodité. L'étude a inclus 32 receveurs d'une greffe rénale et 11 FSS. MÉTHODOLOGIE: Sept groupes de discussion (5 avec les receveurs, 2 avec les FSS) ont été organisés pour guider le développement de l'application. Les séances ont été enregistrées et les transcriptions ont été codées afin de préciser les thèmes. RÉSULTATS: Le développement d'une application pour améliorer l'observance au traitement n'était pas une priorité pour les FSS. Les receveurs d'une greffe priorisaient d'avoir le choix : ils souhaitaient que toutes les fonctionnalités soient facultatives. Les receveurs d'une greffe avaient une préférence pour une application qui offrirait du soutien lors de leurs déplacements, qui permettrait un accès aux résultats de laboratoire et qui soit utilisée par les nouveaux greffés et les receveurs plus jeunes. Tous les participants préféraient que l'application propose un lien vers la pharmacie et qu'elle favorise l'autogestion et la responsabilisation.Pour que l'application améliore la communication, les FSS étaient d'avis qu'il fallait s'attarder aux priorités suivantes : la clarté de la portée de l'application; les obligations juridiques, éthiques et professionnelles; et la tenue des dossiers. Tant les receveurs d'une greffe que les FSS accordaient une priorité à la charge de travail des professionnels de la santé et aux préoccupations plus générales en matière de santé et de médicaments. Les FSS préféraient une assistance technique; et tous les participants avaient une préférence pour que l'application soit accessible aux FSS ne travaillant pas en transplantation. LIMITES: Parmi les limites figurent la sous-représentation des médecins, l'absence de receveurs issus de la diversité raciale/ethnique et un possible biais de sélection des receveurs d'une greffe qui se perçoivent comme adhérant à leur traitement immunosuppresseur. CONCLUSION: D'autres recherches sont nécessaires pour que l'application devienne une plateforme complète et sécurisée qui facilite la communication entre les patients, les professionnels de la santé, les pharmacies et les cliniciens ne travaillant pas en transplantation, tout en allégeant la charge de travail des fournisseurs de soins.

Inter- and intradialytic fluid volume changes and vascular stiffness parameters in patients on hemodialysis.

BACKGROUND: Whether fluid overload is associated with vascular stiffness parameters in hemodialysis (HD) patients has not been fully elucidated. We hypothesized that interdialytic fluid accumulation increases vascular stiffness parameters, which improves with intradialytic ultrafiltration. METHODS: Fluid overload and vascular stiffness parameters were assessed in 39 HD patients (20 with and 19 without fluid overload) and compared to 26 healthy controls. Fluid status was assessed 15 minutes before the mid-week HD session by bio-impedance spectroscopy. Following this, ambulatory pulse wave velocity (PWV) and augmentation index (AIx) were measured for 24 hours before another mid-week HD session and then for 5 hours starting 30 minutes before and ending 30 minutes after the session. RESULTS: HD patients had significant fluid overload compared to healthy controls (2.0±2.4 vs. -0.2±0.6 L; P<0.001) and baseline PWV was higher (10.3±1.7 vs. 8.8±1.4 m/s; P<0.001). There was no significant difference between PWV and AIx in fluid overloaded and non-fluid overloaded HD patients prior to, or during the HD session. AIx of non-fluid overloaded HD patients improved after the HD session (P = 0.04). Average 24-hour AIx was higher in fluid overloaded HD patients (P<0.001). CONCLUSIONS: Inter- and intradialytic changes in fluid volume were only weakly related to vascular stiffness parameters in HD patients. Although there was a modest reduction in AIx in non-fluid overloaded HD patients after the dialysis session, fluid removal did not improve vascular stiffness parameters during the HD session. We speculate that the effect of fluid overload correction on vascular stiffness parameters requires long-term adjustments in the vasculature.

Angiotensin II and the Renal Hemodynamic Response to an Isolated Increased Renal Venous Pressure in Rats.

Elevated central venous pressure increases renal venous pressure (RVP) which can affect kidney function. We previously demonstrated that increased RVP reduces renal blood flow (RBF), glomerular filtration rate (GFR), and renal vascular conductance (RVC). We now investigate whether the RAS and RBF autoregulation are involved in the renal hemodynamic response to increased RVP. Angiotensin II (ANG II) levels were clamped by infusion of ANG II after administration of an angiotensin-converting enzyme (ACE) inhibitor in male Lewis rats. This did not prevent the decrease in ipsilateral RBF (-1.9±0.4ml/min, p<0.05) and GFR (-0.77±0.18ml/min, p<0.05) upon increased RVP; however, it prevented the reduction in RVC entirely. Systemically, the RVP-induced decline in mean arterial pressure (MAP) was more pronounced in ANG II clamped animals vs. controls (-22.4±4.1 vs. -9.9±2.3mmHg, p<0.05), whereas the decrease in heart rate (HR) was less (-5±6bpm vs. -23±4bpm, p<0.05). In animals given vasopressin to maintain a comparable MAP after ACE inhibition (ACEi), increased RVP did not impact MAP and HR. RVC also did not change (0.018±0.008ml/minˑmmHg), and the reduction of GFR was no longer significant (-0.54±0.15ml/min). Furthermore, RBF autoregulation remained intact and was reset to a lower level when RVP was increased. In conclusion, RVP-induced renal vasoconstriction is attenuated when ANG II is clamped or inhibited. The systemic effect of increased RVP, a decrease in HR related to a mild decrease in blood pressure, is attenuated also during ANG II clamp. Last, RBF autoregulation remains intact when RVP is elevated and is reduced to lower levels of RBF. This suggests that in venous congestion, the intact RBF autoregulation could be partially responsible for the vasoconstriction.

Impact of home telemonitoring and management support on blood pressure control in non-dialysis CKD: a systematic review protocol.

INTRODUCTION: Hypertension is a common public health problem and a key modifiable risk factor for cardiovascular (CV) and chronic kidney disease (CKD). Home blood pressure (BP) telemonitoring (HBPT) and management is associated with improved BP control, accelerated delivery of care and decision-making strategies that can reduce adverse outcomes associated with hypertension. The aim of this paper is to describe the protocol for a systematic review to assess the impact of HBPT interventions used for improving BP control and reducing CV and kidney outcomes in non-dialysis CKD patients. METHODS: We developed this protocol using the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Protocols 2015. We will search empirical databases such as MEDLINE, Embase, Cochrane Library, CINAHL, Web of Science and PsycINFO and grey literature for studies conducted in non-dialysis CKD patients on interventions using HBPT and reporting outcomes related to BP control and other outcomes such as CV events and kidney disease progression. All studies meeting these criteria, in adults and published from inception until 2020 with no language barrier will be included. ETHICS AND DISSEMINATION: Ethical approval will not be required for this review as the data used will be extracted from already published studies with publicly accessible data. As this study will assess the impact of HBPT on BP control in non-dialysis CKD patients, evidence gathered through it will be disseminated using traditional approaches that includes open-access peer-reviewed publication, scientific presentations and a report. We will also disseminate our findings to appropriate government agencies. PROSPERO REGISTRATION NUMBER: CRD42020190705).

Tubuloglomerular Feedback Synchronization in Nephrovascular Networks.

To perform their functions, the kidneys maintain stable blood perfusion in the face of fluctuations in systemic BP. This is done through autoregulation of blood flow by the generic myogenic response and the kidney-specific tubuloglomerular feedback (TGF) mechanism. The central theme of this paper is that, to achieve autoregulation, nephrons do not work as single units to manage their individual blood flows, but rather communicate electrically over long distances to other nephrons via the vascular tree. Accordingly, we define the nephrovascular unit (NVU) to be a structure consisting of the nephron, glomerulus, afferent arteriole, and efferent arteriole. We discuss features that require and enable distributed autoregulation mediated by TGF across the kidney. These features include the highly variable topology of the renal vasculature which creates variability in circulation and the potential for mismatch between tubular oxygen demand and delivery; the self-sustained oscillations in each NVU arising from the autoregulatory mechanisms; and the presence of extensive gap junctions formed by connexins and their properties that enable long-distance transmission of TGF signals. The existence of TGF synchronization across the renal microvascular network enables an understanding of how NVUs optimize oxygenation-perfusion matching while preventing transmission of high systemic pressure to the glomeruli, which could lead to progressive glomerular and vascular injury.

Fluid management in chronic kidney disease: what is too much, what is the distribution, and how to manage fluid overload in patients with chronic kidney disease?

PURPOSE OF REVIEW: Assessment of fluid status to reach normovolemia in patients with chronic kidney disease (CKD) continues to be a tough task. Besides clinical observation, technological methods have been introduced, yet, the best approach is still uncertain. The present review looks at fluid overload in CKD from three perspectives: the critical fluid threshold leading to adverse cardiovascular outcomes, fluid distribution and its clinical correlates, and direct effect of fluid overload on vascular function related to disturbance of the sodium-skin axis and endothelial glycocalyx dysfunction. RECENT FINDINGS: To determine fluid status, both the absolute and relative fluid overload is used as parameter in clinical practice. In addition, the definition of fluid overload is ambivalent and its relation to symptom burden has not been studied well. Studies on the impact of distribution of fluid are scarce and the limited evidence suggests differences based on the cause of CKD. So far, no standardized technologies are available to adequately determine fluid distribution. After discovering the 'third compartment' of total body sodium in skin and muscle tissue and its potential direct effect on vascular function, other biomarkers such as VEGF-C are promising. SUMMARY: We propose a multimodal clinical approach for volume management in CKD. Because there are currently no studies are available demonstrating that correction of fluid overload in CKD will lead to better outcome, these are strongly needed.

Chronic elevation of renal venous pressure induces extensive renal venous collateral formation and modulates renal function and cardiovascular stability in rats.

Acutely increased renal venous pressure (RVP) impairs renal function, but the long-term impact is unknown. We investigated whether chronic RVP elevation impairs baseline renal function and prevents exacerbation of renal dysfunction and cardiovascular instability upon further RVP increase. RVP elevation (20-25 mmHg) or sham operation (sham) was performed in rats. After 1 wk (n = 17) or 3 wk (n = 22), blood pressure, RVP, renal blood flow (RBF), renal vascular conductance (RVC), and glomerular filtration rate (GFR) were measured at baseline and during superimposed RVP increase. Chronic RVP elevation induced extensive renal venous collateral formation. RVP fell to 6 ± 1 mmHg at 1 wk and 3 ± 1 mmHg at 3 wk. Baseline blood pressure and heart rate were unaltered compared with sham. RBF, RVC, and GFR were reduced at 1 wk but normalized by 3 wk. Upon further RVP increase, the drop in mean arterial pressure was attenuated at 3 wk compared with 1 wk (P < 0.05), whereas heart rate fell comparably across all groups; the mean arterial pressure-heart rate relationship was disrupted at 1 and 3 wk. RBF fell to a similar degree as sham at 1 wk (-2.3 ± 0.7 vs. -3.9 ± 1.2 mL/min, P = 0.066); however, at 3 wk, this was attenuated compared with sham (-1.5 ± 0.5 vs. -4.2 ± 0.7 mL/min, P < 0.05). The drop in RVC and GFR was attenuated at 1 and 3 wk (P < 0.05). Thus, chronic RVP elevation induced by partial renal vein ligation elicits extensive renal venous collateral formation, and although baseline renal function is impaired, chronic RVP elevation in this manner induces protective adaptations in kidneys of healthy rats, which attenuates the hemodynamic response to further RVP increase.

Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3 (Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure.

BACKGROUND: Although empagliflozin was shown to profoundly reduce cardiovascular events in diabetic patients and blunt the decline in cardiac function in nondiabetic mice with established heart failure (HF), the mechanism of action remains unknown. METHODS AND RESULTS: We treated 2 rodent models of HF with 10 mg/kg per day empagliflozin and measured activation of the NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome in the heart. We show for the first time that beneficial effects of empagliflozin in HF with reduced ejection fraction (HF with reduced ejection fraction [HFrEF]; n=30-34) occur in the absence of changes in circulating ketone bodies, cardiac ketone oxidation, or increased cardiac ATP production. Of note, empagliflozin attenuated activation of the NLRP3 inflammasome and expression of associated markers of sterile inflammation in hearts from mice with HFrEF, implicating reduced cardiac inflammation as a mechanism of empagliflozin that contributes to sustained function in HFrEF in the absence of diabetes mellitus. In addition, we validate that the beneficial cardiac effects of empagliflozin in HF with preserved ejection fraction (HFpEF; n=9-10) are similarly associated with reduced activation of the NLRP3 inflammasome. Lastly, the ability of empagliflozin to reduce inflammation was completely blunted by a calcium (Ca2+) ionophore, suggesting that empagliflozin exerts its benefit upon restoring optimal cytoplasmic Ca2+ levels in the heart. CONCLUSIONS: These data provide evidence that the beneficial cardiac effects of empagliflozin are associated with reduced cardiac inflammation via blunting activation of the NLRP3 inflammasome in a Ca2+-dependent manner and hence may be beneficial in treating HF even in the absence of diabetes mellitus.