Sympathetic overactivity in dialysis patients-Underappreciated and clinically consequential.

Cardiovascular morbidity and mortality remain frustratingly common in dialysis patients. A dearth of established evidence-based treatment calls for alternative therapeutic avenues to be embraced. Sympathetic hyperactivity, predominantly due to afferent nerve signaling from the diseased native kidneys, has been established to be prognostic in the dialysis population for over 15 years. Despite this, tangible therapeutic interventions have, to date, been unsuccessful and the outlook for patients remains poor. This narrative review summarizes established experimental and clinical data, highlighting recent developments, and proposes why interventions to ameliorate sympathetic hyperactivity may well be beneficial for this high-risk population.

Early Ultrasound Surveillance of Newly-Created Hemodialysis Arteriovenous Fistula.

Introduction: We assess if ultrasound surveillance of newly-created arteriovenous fistulas (AVFs) can predict nonmaturation sufficiently reliably to justify randomized controlled trial (RCT) evaluation of ultrasound-directed salvage intervention. Methods: Consenting adults underwent blinded fortnightly ultrasound scanning of their AVF after creation, with scan characteristics that predicted AVF nonmaturation identified by logistic regression modeling. Results: Of 333 AVFs created, 65.8% matured by 10 weeks. Serial scanning revealed that maturation occurred rapidly, whereas consistently lower fistula flow rates and venous diameters were observed in those that did not mature. Wrist and elbow AVF nonmaturation could be optimally modeled from week 4 ultrasound parameters alone, but with only moderate positive predictive values (PPVs) (wrist, 60.6% [95% confidence interval, CI: 43.9-77.3]; elbow, 66.7% [48.9-84.4]). Moreover, 40 (70.2%) of the 57 AVFs that thrombosed by week 10 had already failed by the week 4 scan, thus limiting the potential of salvage procedures initiated by that scan's findings to alter overall maturation rates. Modeling of the early ultrasound characteristics could also predict primary patency failure at 6 months; however, that model performed poorly at predicting assisted primary failure (those AVFs that failed despite a salvage attempt), partly because patency of at-risk AVFs was maintained by successful salvage performed without recourse to the early scan data. Conclusion: Early ultrasound surveillance may predict fistula maturation, but is likely, at best, to result in only very modest improvements in fistula patency. Power calculations suggest that an impractically large number of participants (>1700) would be required for formal RCT evaluation.

Doppler ultrasound surveillance of recently formed haemodialysis arteriovenous fistula: the SONAR observational cohort study.

Background: Arteriovenous fistulas are considered the best option for haemodialysis provision, but as many as 30% fail to mature or suffer early failure. Objective: To assess the feasibility of performing a randomised controlled trial that examines whether, by informing early and effective salvage intervention of fistulas that would otherwise fail, Doppler ultrasound surveillance of developing arteriovenous fistulas improves longer-term arteriovenous fistula patency. Design: A prospective multicentre observational cohort study (the 'SONAR' study). Setting: Seventeen haemodialysis centres in the UK. Participants: Consenting adults with end-stage renal disease who were scheduled to have an arteriovenous fistula created. Intervention: Participants underwent Doppler ultrasound surveillance of their arteriovenous fistulas at 2, 4, 6 and 10 weeks after creation, with clinical teams blinded to the ultrasound surveillance findings. Main outcome measures: Fistula maturation at week 10 defined according to ultrasound surveillance parameters of representative venous diameter and blood flow (wrist arteriovenous fistulas: ≥ 4 mm and > 400 ml/minute; elbow arteriovenous fistulas: ≥ 5 mm and > 500 ml/minute). Mixed multivariable logistic regression modelling of the early ultrasound scan data was used to predict arteriovenous fistula non-maturation by 10 weeks and fistula failure at 6 months. Results: A total of 333 arteriovenous fistulas were created during the study window (47.7% wrist, 52.3% elbow). By 2 weeks, 37 (11.1%) arteriovenous fistulas had failed (thrombosed), but by 10 weeks, 219 of 333 (65.8%) of created arteriovenous fistulas had reached maturity (60.4% wrist, 67.2% elbow). Persistently lower flow rates and venous diameters were observed in those fistulas that did not mature. Models for arteriovenous fistulas' non-maturation could be optimally constructed using the week 4 scan data, with fistula venous diameter and flow rate the most significant variables in explaining wrist fistula maturity failure (positive predictive value 60.6%, 95% confidence interval 43.9% to 77.3%), whereas resistance index and flow rate were most significant for elbow arteriovenous fistulas (positive predictive value 66.7%, 95% confidence interval 48.9% to 84.4%). In contrast to non-maturation, both models predicted fistula maturation much more reliably [negative predictive values of 95.4% (95% confidence interval 91.0% to 99.8%) and 95.6% (95% confidence interval 91.8% to 99.4%) for wrist and elbow, respectively]. Additional follow-up and modelling on a subset (n = 192) of the original SONAR cohort (the SONAR-12M study) revealed the rates of primary, assisted primary and secondary patency arteriovenous fistulas at 6 months were 76.5, 80.7 and 83.3, respectively. Fistula vein size, flow rate and resistance index could identify primary patency failure at 6 months, with similar predictive power as for 10-week arteriovenous fistula maturity failure, but with wide confidence intervals for wrist (positive predictive value 72.7%, 95% confidence interval 46.4% to 99.0%) and elbow (positive predictive value 57.1%, 95% confidence interval 20.5% to 93.8%). These models, moreover, performed poorly at identifying assisted primary and secondary patency failure, likely because a subset of those arteriovenous fistulas identified on ultrasound surveillance as at risk underwent subsequent successful salvage intervention without recourse to early ultrasound data. Conclusions: Although early ultrasound can predict fistula maturation and longer-term patency very effectively, it was only moderately good at identifying those fistulas likely to remain immature or to fail within 6 months. Allied to the better- than-expected fistula patency rates achieved (that are further improved by successful salvage), we estimate that a randomised controlled trial comparing early ultrasound-guided intervention against standard care would require at least 1300 fistulas and would achieve only minimal patient benefit. Trial Registration: This trial is registered as ISRCTN36033877 and ISRCTN17399438. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR135572) and is published in full in Health Technology Assessment; Vol. 28, No. 24. See the NIHR Funding and Awards website for further award information.

For people with advanced kidney disease, haemodialysis is best provided by an 'arteriovenous fistula', which is created surgically by joining a vein onto an artery at the wrist or elbow. However, these take about 2 months to develop fully ('mature'), and as many as 3 out of 10 fail to do so. We asked whether we could use early ultrasound scanning of the fistula to identify those that are unlikely to mature. This would allow us to decide whether it would be practical to run a large, randomised trial to find out if using early ultrasound allows us to 'rescue' fistulas that would otherwise fail. We invited adults to undergo serial ultrasound scanning of their fistula in the first few weeks after it was created. We then analysed whether we could use the data from the early scans to identify those fistulas that were not going to mature by week 10. Of the 333 fistulas that were created, about two-thirds reached maturity by week 10. We found that an ultrasound scan 4 weeks after fistula creation could reliably identify those fistulas that were going to mature. However, of those fistulas predicted to fail, about one-third did eventually mature without further intervention, and even without knowing what the early scans showed, another third were successfully rescued by surgery or X-ray-guided treatment at a later stage. Performing an early ultrasound scan on a fistula can provide reassurance that it will mature and deliver trouble-free dialysis. However, because scans are poor at identifying fistulas that are unlikely to mature, we would not recommend their use to justify early surgery or X-ray-guided treatment in the expectation that this will improve outcomes.

Differential cellular and humoral immune responses in immunocompromised individuals following multiple SARS-CoV-2 vaccinations.

Introduction: The heterogeneity of the immunocompromised population means some individuals may exhibit variable, weak or reduced vaccine-induced immune responses, leaving them poorly protected from COVID-19 disease despite receiving multiple SARS-CoV-2 vaccinations. There is conflicting data on the immunogenicity elicited by multiple vaccinations in immunocompromised groups. The aim of this study was to measure both humoral and cellular vaccine-induced immunity in several immunocompromised cohorts and to compare them to immunocompetent controls. Methods: Cytokine release in peptide-stimulated whole blood, and neutralising antibody and baseline SARS-CoV-2 spike-specific IgG levels in plasma were measured in rheumatology patients (n=29), renal transplant recipients (n=46), people living with HIV (PLWH) (n=27) and immunocompetent participants (n=64) post third or fourth vaccination from just one blood sample. Cytokines were measured by ELISA and multiplex array. Neutralising antibody levels in plasma were determined by a 50% neutralising antibody titre assay and SARS-CoV-2 spike specific IgG levels were quantified by ELISA. Results: In infection negative donors, IFN-γ, IL-2 and neutralising antibody levels were significantly reduced in rheumatology patients (p=0.0014, p=0.0415, p=0.0319, respectively) and renal transplant recipients (p<0.0001, p=0.0005, p<0.0001, respectively) compared to immunocompetent controls, with IgG antibody responses similarly affected. Conversely, cellular and humoral immune responses were not impaired in PLWH, or between individuals from all groups with previous SARS-CoV-2 infections. Discussion: These results suggest that specific subgroups within immunocompromised cohorts could benefit from distinct, personalised immunisation or treatment strategies. Identification of vaccine non-responders could be critical to protect those most at risk.

Delivery of Radioiodine Ablation in a Patient with End-Stage Renal Disease.

This case presents a pragmatic approach to the management of a radioiodine remnant ablation patient on hemodialysis which required no pretherapeutic dosimetric measurements. Pretreatment radiation dose modeling was performed using literature values for radioiodine hemodialysis extraction efficacies to determine a safe treatment regimen including adjustment of the administered activity and hemodialysis frequency. The pretreatment modeling was subsequently verified using external and blood radiation monitoring during treatment.

Pulmonary vein isolation combined with spironolactone or renal sympathetic denervation in patients with chronic kidney disease, uncontrolled hypertension, paroxysmal atrial fibrillation, and a pacemaker.

BACKGROUND: Atrial fibrillation (AF) commonly occurs in chronic kidney disease (CKD), occasioning adverse outcomes. Merging pulmonary vein isolation (PVI) and renal sympathetic denervation (RSD) may decrease the recurrence of AF in subjects with CKD and uncontrolled hypertension. We considered that RSD could reduce the recurrence of AF in patients with CKD by modulating sympathetic hyperactivity. We aimed to evaluate the impact of RSD or spironolactone 50 mg/day associated with PVI in reducing systolic blood pressure (BP), AF recurrence, and AF burden in patients with a history of paroxysmal AF and mild CKD. METHODS: This was a single-center, prospective, longitudinal, randomized, double-blind study. The individuals were randomly divided into two groups (PVI + spironolactone, n = 36, and PVI + RSD, n = 33). All of them were followed for exactly 1 year to assess maintenance of sinus rhythm and to monitor the other variables. RESULTS: Ambulatory BP measurements were reduced in both groups and at the 12th month also differed between groups. Significantly more patients in the PVI + RSD (61%) than in the PVI + spironolactone group (36%) were AF-free at the 12th month of follow-up, P = 0.0242. Toward the end of the study, the mean AF burden was lower in the PVI + RSD group as compared to PVI + spironolactone group, at the 9th month: ∆ = - 10% (P < 0.0001), and at the 12th month: ∆ = - 12% (P < 0.0001), respectively. CONCLUSIONS: PVI + RSD is safe and appears to be superior to PVI + spironolactone in BP reduction, augmentation of AF event-free rate, reduction of AF burden, and improvement of renal function.

The effects of different physical activities on atrial fibrillation in patients with hypertension and chronic kidney disease.

BACKGROUND: Atrial fibrillation (AF) is highly common, and is most frequently observed in individuals with hypertension and structural cardiac disease. Sympathetic hyperactivity plays a fundamental role in the progression, maintenance and aggravation of arrhythmia. Endurance exercise training clearly lowers sympathetic activity in sympathoexcitatory disease states, and is well-tolerated by patients with chronic kidney disease (CKD). METHODS: We assessed 50 CKD patients with hypertension. Each patient provided a complete medical history and underwent a physical examination. We used an implantable cardiac monitor over a 3-year follow-up period to evaluate the effects of high-intensity interval training (HIIT) and moderate exercise (ModEx) physical activity protocols on AF occurrence, and determined the effectiveness of these protocols in improving renal function. Subjects were followed up every 6 months after the beginning of the intervention. RESULTS: During the 3-year follow-up, AF onset was higher in CKD patients who engaged in HIIT (72%) than in those who engaged in ModEx (24%) (hazard ratio, 3.847; 95% confidence interval, 1.694-8.740, P = 0.0013 by log-rank test). Both groups exhibited significant intra-group changes in the mean systolic 24-hour ambulatory blood pressure measurements (ABPM) between baseline and 12, 24, and 36 months. There were also significant differences in the mean systolic 24-hour ABPM between the groups at the same time points. CONCLUSION: In CKD patients with hypertension, improvements in AF onset, renal function and some echocardiographic parameters were more evident in subjects who engaged in ModEx than in those who engaged in HIIT during 3 years of follow-up.

Endovascular Renal Denervation in End-Stage Kidney Disease Patients: Cardiovascular Protection-A Proof-of-Concept Study.

INTRODUCTION: Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. METHODS: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. RESULTS: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 95% CI [-47, -8]) were reduced. Mean ambulatory BP (systolic: -24 mm Hg, 95% CI [-42, -5] and diastolic: -13 mm Hg, 95% CI [-22, -4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: -25 mm Hg, 95% CI [-45, -5] and diastolic: -13 mm Hg, 95% CI [-24, -1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. DISCUSSION: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

Endovascular renal denervation: a novel sympatholytic with relevance to chronic kidney disease.

Endovascular renal denervation (sympathectomy) is a novel procedure developed for the treatment of resistant hypertension. Evidence suggests that it reduces both afferent and efferent sympathetic nerve activity, which may offer clinical benefit over and above any blood pressure-lowering effect. Studies have shown objective improvements in left ventricular mass, ventricular function, central arterial stiffness, central haemodynamics, baroreflex sensitivity and arrhythmia frequency. Benefits have also been seen in insulin resistance, microalbuminuria and glomerular filtration rate. In chronic kidney disease, elevated sympathetic activity has been causally linked to disease progression and cardiovascular sequelae. Effecting a marked reduction in sympathetic hyperactivity may herald a significant step in the management of this and other conditions. In this in-depth review, the pathophysiology and clinical significance of the sympatholytic effects of endovascular renal denervation are discussed.