Microparticles and exercise in clinical populations

Microparticles (MPs) are shed membrane vesicles released from a variety of cell types in response to cellular activation or apoptosis. They are elevated in a wide variety of disease states and have been previously measured to assess both disease activity and severity. However, recent research suggests that they also possess bioeffector functions, including but not limited to promoting coagulation and thrombosis, inducing endothelial dysfunction, increasing pro‐inflammatory cytokine release and driving angiogenesis, thereby increasing cardiovascular risk. Current evidence suggests that exercise may reduce both the number and pathophysiological potential of circulating MPs, making them an attractive therapeutic target. However, the existing body of literature is largely comprised of in vitro or animal studies and thus drawing meaningful conclusions with regards to health and disease remains difficult. In this review, we highlight the role of microparticles in disease, comment on the use of exercise and dietary manipulation as a therapeutic strategy, and suggest future research directions that would serve to address some of the limitations present in the research to date

The impact of exercising during haemodialysis on blood pressure, markers of cardiac injury and systemic inflammation - preliminary results of a pilot study

Background/Aims: Patients requiring haemodialysis have cardiovascular and immune dysfunction. Little is known about the acute effects of exercise during haemodialysis. Exercise has numerous health benefits but in other populations has a profound impact upon blood pressure, inflammation and immune function; therefore having the potential to exacerbate cardiovascular and immune dysfunction in this vulnerable population. Methods: Fifteen patients took part in a randomised-crossover study investigating the effect of a 30-min bout of exercise during haemodialysis compared to resting haemodialysis. We assessed blood pressure, plasma markers of cardiac injury and systemic inflammation and neutrophil degranulation. Results: Exercise increased blood pressure immediately post-exercise; however, 1 hour after exercise blood pressure was lower than resting levels (106±22 vs. 117±25 mm Hg). No differences in h-FABP, cTnI, myoglobin or CKMB were observed between trial arms. Exercise did not alter circulating concentrations of IL-6, TNF-α or IL-1ra nor clearly suppress neutrophil function. Conclusions: This study demonstrates fluctuations in blood pressure during haemodialysis in response to exercise. However, since the fall in blood pressure occurred without evidence of cardiac injury, we regard it as a normal response to exercise superimposed onto the haemodynamic response to haemodialysis. Importantly, exercise did not exacerbate systemic inflammation or immune dysfunction; intradialytic exercise was well tolerated

Regular exercise during haemodialysis promotes an anti-inflammatory leucocyte profile

Background Cardiovascular disease (CVD) is the most common cause of mortality in haemodialysis (HD) patients and is highly predicted by markers of chronic inflammation. Regular exercise may have beneficial anti-inflammatory effects, but this is unclear in HD patients. This study assessed the effect of regular intradialytic exercise on soluble inflammatory factors and inflammatory leukocyte phenotypes. Methods Twenty-two HD patients from a centre where intradialytic cycling was offered thrice-weekly and 16 HD patients receiving usual care volunteered. Exercising patients aimed to cycle for 30 min at RPE of “somewhat hard”. Baseline characteristic were compared with 16 healthy age-matched individuals. Physical function, soluble inflammatory markers and leukocyte phenotypes were assessed again after 6 months of regular exercise. Results Patients were less active than their healthy counterparts and had significant elevations in measures of inflammation (IL-6, CRP, TNF-α, intermediate and non-classical monocytes; all P<0.001). Six months of regular intradialytic exercise improved physical function (sit-to-stand 60). After 6 months the proportion of intermediate monocytes in the exercising patients reduced compared to non-exercisers (7.58±1.68 to 6.38±1.81% vs. 6.86±1.45 to 7.88±1.66%; P<0.01). Numbers (but not proportion) of regulatory T cells decreased in the non-exercising patients only (P<0.05). Training had no significant effect on circulating IL-6, CRP or TNF-α concentrations. Conclusions These findings suggest regular intradialytic exercise is associated with an anti-inflammatory effect at a circulating cellular level but not in circulating cytokines. This may be protective against the increased risk of CVD and mortality that is associated with chronic inflammation and elevated numbers of intermediate monocytes

An increase in circulating monocyte and platelet derived microparticles during haemodialysis

An increase in circulating monocyte and platelet derived microparticles during haemodialysi

Defining myocardial fibrosis in haemodialysis patients with non-contrast cardiac magnetic resonance

Background: Extent of myocardial fibrosis (MF) determined using late gadolinium enhanced (LGE) predicts outcomes, but gadolinium is contraindicated in advanced renal disease. We assessed the ability of native T1-mapping to identify and quantify MF in aortic stenosis patients (AS) as a model for use in haemodialysis patients. Methods: We compared the ability to identify areas of replacement-MF using native T1-mapping to LGE in 25 AS patients at 3 T. We assessed agreement between extent of MF defined by LGE full-width-half-maximum (FWHM) and the LGE 3-standard-deviations (3SD) in AS patients and nine T1 thresholding-techniques, with thresholds set 2-to-9 standard-deviations above normal-range (1083 ± 33 ms). A further technique was tested that set an individual T1-threshold for each patient (T11SD). The technique that agreed most strongly with FWHM or 3SD in AS patients was used to compare extent of MF between AS (n = 25) and haemodialysis patients (n = 25). Results: Twenty-six areas of enhancement were identified on LGE images, with 25 corresponding areas of discretely increased native T1 signal identified on T1 maps. Global T1 was higher in haemodialysis than AS patients (1279 ms ± 5. 8 vs 1143 ms ± 12.49, P < 0.01). No signal-threshold technique derived from standard-deviations above normal-range associated with FWHM or 3SD. T11SD correlated with FWHM in AS patients (r = 0.55) with moderate agreement (ICC = 0.64), (but not with 3SD). Extent of MF defined by T11SD was higher in haemodialysis vs AS patients (21.92% ± 1 vs 18.24% ± 1.4, P = 0.038), as was T1 in regions-of-interest defined as scar (1390 ± 8.7 vs 1276 ms ± 20.5, P < 0.01). There was no difference in the relative difference between remote myocardium and regions defined as scar, between groups (111.4 ms ± 7.6 vs 133.2 ms ± 17.5, P = 0.26). Conclusions: Areas of MF are identifiable on native T1 maps, but absolute thresholds to define extent of MF could not be determined. Histological studies are needed to assess the ability of native-T1 signal-thresholding techniques to define extent of MF in haemodialysis patients. Data is taken from the PRIMID-AS (NCT01658345) and CYCLE-HD studies (ISRCTN11299707

Implementing a theory-based intradialytic exercise programme in practice: a quality improvement project

Background Research evidence outlines the benefits of intradialytic exercise (IDE), yet implementation into practice has been slow, ostensibly due to lack of patient and staff engagement. The aim of this quality improvement project was to improve patient outcomes via the introduction of an IDE programme; evaluate patient uptake, sustainability and enhance the engagement of routine haemodialysis (HD) staff with the delivery of the IDE programme. Methods We developed and refined an IDE programme, including interventions designed to increase patient and staff engagement that were based upon the Theoretical Domains Framework, using a series of ‘Plan, Do, Study, Act’ cycles. The programme was introduced at two UK NHS HD units. Process measures included patient uptake, withdrawals, adherence and HD staff involvement. Outcomes measures were patient-reported functional capacity, anxiety, depression and symptomology. All measures were collected over 12 months. Results 95 patients enrolled in the IDE programme. 64 (75%) were still participating at three months, dropping to 41 (48%) at 12 months. Adherence was high (78%) at three months, dropping to 63% by 12 months. Provision of IDE by HD staff accounted for a mean of 2 (5%) sessions per three-month time point. Patients displayed significant improvements in functional ability (p=0.01), and reduction in depression (p=0.02) over 12 months, but effects seen were limited to those who completed the programme. Conclusions A theory-based IDE programme is feasible and leads to improvement in functional capacity and depression. Sustaining IDE over time is marred by high levels of patient withdrawal from the programme. Significant change at an organisational level is required to enhance sustainability by increasing HD staff engagement or access to exercise professional support

Native T1 mapping: inter-study, inter-observer and inter-center reproducibility in hemodialysis patients

Background Native T1 mapping is a cardiovascular magnetic resonance (CMR) technique that associates with markers of fibrosis and strain in hemodialysis patients. The reproducibility of T1 mapping in hemodialysis patients, prone to changes in fluid status, is unknown. Accurate quantification of myocardial fibrosis in this population has prognostic potential. Methods Using 3 Tesla CMR, we report the results of 1) the inter-study, inter-observer and intra-observer reproducibility of native T1 mapping in 10 hemodialysis patients; 2) inter-study reproducibility of left ventricular (LV) structure and function in 10 hemodialysis patients; 3) the agreement of native T1 map and native T1 phantom analyses between two centres in 20 hemodialysis patients; 4) the effect of changes in markers of fluid status on native T1 values in 10 hemodialysis patients. Results Inter-study, inter-observer and intra-observer variability of native T1 mapping were excellent with co-efficients of variation (CoV) of 0.7, 0.3 and 0.4% respectively. Inter-study CoV for LV structure and function were: LV mass = 1%; ejection fraction = 1.1%; LV end-diastolic volume = 5.2%; LV end-systolic volume = 5.6%. Inter-centre variability of analysis techniques were excellent with CoV for basal and mid-native T1 slices between 0.8–1.2%. Phantom analyses showed comparable native T1 times between centres, despite different scanners and acquisition sequences (centre 1: 1192.7 ± 7.5 ms, centre 2: 1205.5 ± 5 ms). For the 10 patients who underwent inter-study testing, change in body weight (Δweight) between scans correlated with change in LV end-diastolic volume (ΔLVEDV) (r = 0.682;P = 0.03) representing altered fluid status between scans. There were no correlations between change in native T1 between scans (ΔT1) and ΔLVEDV or Δweight (P > 0.6). Linear regression confirmed ΔT1 was unaffected by ΔLVEDV or Δweight (P > 0.59). Conclusions Myocardial native T1 is reproducible in HD patients and unaffected by changes in fluid status at the levels we observed. Native T1 mapping is a potential imaging biomarker for myocardial fibrosis in patients with end-stage renal disease

The efficacy of prebiotic, probiotic and synbiotic supplementation in modulating gut-derived circulatory particles associated with cardiovascular disease in individuals receiving dialysis: a systematic review and meta-analysis of randomized controlled trials

ObjectiveThis systematic review and meta-analyses provide an up-to-date synthesis on the effects of supplementation on circulating levels of toxic metabolites, markers of uremia and inflammation, blood lipids, and other clinical outcomes.MethodsSeventeen databases were searched, supplemented with internet and hand searching. Randomized controlled trials of adult end-stage renal-disease individuals receiving either hemodialysis or peritoneal dialysis were eligible. Trials were restricted to those which had administered a prebiotic, probiotic, or synbiotic as an oral supplement. Primary outcomes were measures of circulating endotoxin, indoxyl-sulphate, and p-cresyl sulfate.ResultsTwenty-one trials were eligible (1152 randomized participants), of which 16 trials were considered to have a high risk of bias. The number of trials available for meta-analysis varied for each primary outcome. Synthesized data indicated that supplementation significantly reduced circulating levels of endotoxin (standardized mean difference, −0.61; 95% confidence interval, −1.03 to −0.20; P = .004; I2 = 0%), indoxyl-sulphate (−0.34; −0.64 to −0.04; P = .02; I2 = 0%), and p-cresyl sulfate (−0.34; −0.61 to −0.07; P = .01; I2 = 0%). For secondary outcomes, supplementation significantly reduced gastrointestinal symptoms (−0.54; −1.02 to −0.07; P = .02; I2 = 0%).ConclusionsSupplementation reduces toxic metabolites associated with cardiovascular disease and mortality in individuals receiving dialysis. However, the majority of trials included were low in quality.</p

Epicardial adipose tissue in patients with end-stage renal disease on haemodialysis.

PURPOSE OF REVIEW: Epicardial adipose tissue (EAT) is the visceral fat of the heart, sharing many of the pathophysiological properties of other visceral fat depots. EAT is a metabolically active paracrine and vasocrine organ that causes local cardiac inflammation and is strongly implicated in the pathogenesis of coronary atherosclerosis. This article highlights the findings of recent observational studies in patients on haemodialysis that link the quantity of EAT to increased rates of cardiovascular and coronary artery disease and review the proposed methods of pathogenesis and the possible role of EAT quantification to improve cardiovascular risk assessment. RECENT FINDINGS: Increasing volumes of EAT in patients on haemodialysis correlate with increased inflammatory mediators, higher rates of cardiovascular disease and coronary artery calcification, independent of general adiposity. EAT is an independent predictor of mortality and a potentially modifiable target for therapeutic interventions. SUMMARY: EAT is likely to play a central role in the pathogenesis of cardiovascular disease in patients on haemodialysis, adds incrementally to conventional cardiovascular risk stratification models and is a potential target for therapeutic intervention

Sometimes when you hear hoof beats, it could be a zebra : consider the diagnosis of Fabry disease

Background: Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of the enzyme α-galactosidase A. Fabry disease is present in 4–5% of men with unexplained left ventricular hypertrophy or cryptogenic stroke. As enzyme replacement therapy is now more widely available, it is important to recognise the signs and symptoms of the disease and establish the diagnosis so that early treatment can be started before irreversible organ damage occurs. Case Presentation: A previously fit and well 32-year-old Caucasian male presented with multisystem dysfunction including renal impairment. Although he had no suggestive symptoms, a diagnosis of Fabry disease was first established on a native renal biopsy. This was confirmed by enzymatic testing and subsequent genetic analysis that revealed a potentially new pathogenic variant. Conclusions: This case highlights the importance both of Fabry disease as a differential diagnosis in patients with renal impairment in the context of multi-system disease and also of adequate tissue sampling for electron microscopy when performing native renal biopsies