Relationship between urinary sodium excretion and serum aldosterone in patients with diabetes in the presence and absence of modifiers of the renin-angiotensin-aldosterone system

Abstract Although low dietary salt intake has beneficial effects on BP (blood pressure), low 24hUNa (24 h urinary sodium excretion), the most accurate estimate of dietary salt intake, is associated with increased mortality in people with diabetes. In the non-diabetic population, low salt intake is associated with increased RAAS (renin-angiotensin-aldosterone system) activity. In this cross-sectional study, we examined the relationship between 24hUNa, PRA (plasma renin activity), serum aldosterone and BNP (brain natriuretic peptide) in patients with diabetes. Clinical characteristics, 24hUNa, PRA, serum aldosterone and BNP were recorded in 222 consecutive patients (77 % with Type 2 diabetes) attending a diabetes clinic at a tertiary hospital. The relationship between 24hUNa, serum aldosterone, PRA, BNP , urinary potassium excretion, serum potassium, serum sodium, eGFR (estimated glomerular filtration rate), urinary albumin excretion and HbA 1c (glycated haemoglobin) was examined by a multivariable regression model. Levels of 24hUNa significantly predicted serum aldosterone in a linear fashion (R 2 = 0.20, P = 0.002). In the subgroup of patients (n = 46) not taking RAAS-modifying agents, this relationship was also observed (R 2 = 0.10, P = 0.03), and the effect of 24hUNa on serum aldosterone was found to be more pronounced than in the whole cohort (coefficient = − 0.0014, compared with − 0.0008). There was no demonstrable relationship between 24hUNa and PRA or BNP . Low 24hUNa is associated with increased serum aldosterone in people with diabetes, in the presence and absence of RAAS-modifying agents. This raises the possibility that stimulation of the RAAS may be a mechanism that contributes to adverse outcomes observed in patients with low 24hUNa

The effect of sodium on sympathetic nervous system activity and endothelial function in people with type 2 diabetes

© 2020 Sara BaqarLowering dietary sodium intake is recommended by public health bodies to lower blood pressure with the ultimate aim of reducing cardiovascular-related disease. However, lower sodium intake has been demonstrated in observational studies to be associated with adverse health outcomes such as higher cardiovascular-related morbidity and mortality in people with type 2 diabetes. They may be due to pleiotropic effects of sodium lowering, such as activation of the renin-angiotensin-aldosterone system (RAAS) and increases in circulating adrenaline and noradrenaline. Dedicated intervention trials are lacking but greatly needed to investigate the complex role of sodium on cardiovascular outcomes further. In an effort to underpin the mechanistic links behind the associations between low sodium intake and poorer cardiovascular outcomes in people with type 2 diabetes, the studies presented in this thesis aimed to examine the effect of sodium on cardiovascular health by measuring the primary endpoints of sympathetic nervous system activity, as assessed by microneurography, and endothelial function, as assessed by endoPAT and endothelial microparticle measurements, and the secondary endpoints of cardiac baroreflex, serum aldosterone, as markers of RAAS activity, and simultaneous measures of 24h blood pressure and heart rate variability. We demonstrated, that compared to other groups along the glucose continuum, individuals with treated type 2 diabetes who had low sodium intake presented with worse endothelial and baroreflex function. This occurred even though these individuals were appropriately managed for their cardio-metabolic risk factors and importantly, adhered to recommended low sodium intake guidelines. This study provided the rationale to conduct an interventional study where, for the first time, we assessed the effect of salt supplementation on cardiovascular endpoints of sympathetic activity and endothelial function as assessed by endoPAT, in people with type 2 diabetes. Salt supplementation was associated with a small increase in sympathetic activity. However, this did not reach levels associated with pathological disease states. Importantly, there were no detrimental effects on endothelial function or alterations in blood pressure. Interestingly improvements in baroreflex function and RAAS activity were seen. When participants were categorized based on salt-sensitivity, salt-resistant individuals demonstrated a trend towards improved endothelial function after salt supplementation. To explore the endothelial response further, we examined the association between habitual sodium intake, RAAS blockade, and endothelial function as assessed by circulating microparticles. Despite expecting higher endothelial microparticles being associated with lower sodium intake, we did not demonstrate any significant association between sodium intake and endothelial microparticles. However, we observed a trend towards higher erythrocyte-derived microparticle levels being associated with lower sodium excretion and higher platelet-derived microparticles being associated with the lowest tertile of 24hUNa excretion. Additionally, RAAS blockade was not associated with lower microparticles counts in the setting of a low sodium intake, questioning whether the therapeutic benefits of RAAS blockade may be attenuated during lower sodium intake. Despite public health bodies advocating for lowering dietary sodium, we demonstrated that these guidelines are simply not being met and sodium intake is unlikely to change over time. Furthermore, we compared the two most common methodologies used to estimate sodium intake in cardiovascular outcome trials which have largely formulated the basis of dietary sodium guidelines. We demonstrated poor agreement between 24h dietary recall and 24h urine sodium excretions, likely due to underestimation and underreporting of sodium intake via 24h dietary recall. Taken together, these findings begin to provide mechanistic insight that sodium lowering in people with type 2 diabetes may not provide the benefit on the sympathetic and endothelial system as intended. Therefore, the necessity for stringent sodium lowering is questioned in this population. Our studies additionally demonstrate the need for future studies to use sound methodological approaches to determine the ideal yet feasible dietary sodium intake targets in people with type 2 diabetes

Strategies for enumeration of circulating microvesicles on a conventional flow cytometer

Enumeration of circulating microvesicles (MVs) by conventional flow cytometry is accomplished by the addition of a known amount of counting beads and calculated from the formula: MV/μl = (MV count/bead count) × final bead concentration. We sought to optimize each variable in the equation by determining the best parameters for detecting ‘MV count’ and examining the effects of different bead preparations and concentrations on the final calculation. Three commercially available bead preparations (TruCount, Flow-Count and CountBright) were tested, and MV detection on a BD FACSCanto was optimized for gating by either forward scatter (FSC) or side scatter (SSC); the results were compared by calculating different subsets of MV on a series of 74 typical patient plasma samples. The relationship between the number of beads added to each test and the number of beads counted by flow cytometry remained linear over a wide range of bead concentrations ( R 2 ≥ 0.997). However, TruCount beads produced the most consistent (concentration variation = 3.8%) calculated numbers of plasma CD41 + /Annexin V + MV, which were significantly higher from that calculated using either Flow-Count or CountBright ( p < 0.001). The FACSCanto was able to resolve 0.5 μm beads by FSC and 0.16 μm beads by SSC, but there were significantly more background events using SSC compared with FSC (3113 vs. 470; p = 0.008). In general, sample analysis by SSC resulted in significantly higher numbers of MV ( p < 0.0001) but was well correlated with enumeration by FSC for all MV subtypes ( ρ = 0.62–0.89, p < 0.0001). We conclude that all counting beads provided linear results at concentrations ranging from 6 beads/μl to 100 beads/μl, but TruCount was the most consistent. Using SSC to gate MV events produced high background which negatively affected counting bead enumeration and overall MV calculations. Strategies to reduce SSC background should be employed in order to reliably use this technique

Bowel perforation complicating an ACTH-secreting phaeochromocytoma

ACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing’s syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs. Learning points: • Consider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines. • Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading. • Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma. • Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality

Relationship between urinary sodium excretion and serum aldosterone in patients with diabetes in the presence and absence of modifiers of the renin-angiotensin-aldosterone system

Abstract Although low dietary salt intake has beneficial effects on BP (blood pressure), low 24hUNa (24 h urinary sodium excretion), the most accurate estimate of dietary salt intake, is associated with increased mortality in people with diabetes. In the non-diabetic population, low salt intake is associated with increased RAAS (renin-angiotensin-aldosterone system) activity. In this cross-sectional study, we examined the relationship between 24hUNa, PRA (plasma renin activity), serum aldosterone and BNP (brain natriuretic peptide) in patients with diabetes. Clinical characteristics, 24hUNa, PRA, serum aldosterone and BNP were recorded in 222 consecutive patients (77 % with Type 2 diabetes) attending a diabetes clinic at a tertiary hospital. The relationship between 24hUNa, serum aldosterone, PRA, BNP , urinary potassium excretion, serum potassium, serum sodium, eGFR (estimated glomerular filtration rate), urinary albumin excretion and HbA 1c (glycated haemoglobin) was examined by a multivariable regression model. Levels of 24hUNa significantly predicted serum aldosterone in a linear fashion (R 2 = 0.20, P = 0.002). In the subgroup of patients (n = 46) not taking RAAS-modifying agents, this relationship was also observed (R 2 = 0.10, P = 0.03), and the effect of 24hUNa on serum aldosterone was found to be more pronounced than in the whole cohort (coefficient = − 0.0014, compared with − 0.0008). There was no demonstrable relationship between 24hUNa and PRA or BNP . Low 24hUNa is associated with increased serum aldosterone in people with diabetes, in the presence and absence of RAAS-modifying agents. This raises the possibility that stimulation of the RAAS may be a mechanism that contributes to adverse outcomes observed in patients with low 24hUNa

Knowledge and attitude of health-care professionals toward adverse drug reactions reporting at King Saud Medical City

Background: Health-care professionals across the globe are obligated to report adverse drug reactions (ADRs). The knowledge of ADRs and attitude of health-care professionals toward ADRs reporting is vital for patient safety. This study intends to investigate the knowledge of ADRs and attitude of health-care professionals toward ADRs reporting. Materials and Methods: A cross-sectional study using an anonymous questionnaire was conducted over a period of 3 months (September 2016 to November 2016) at King Saud Medical City, Riyadh, Saudi Arabia. This study included 399 questionnaires submitted by health-care professionals. Results: A total of 399 questionnaires were submitted by health-care professionals, of which only 14.8% knew the term “ADR” and 55.1% of the respondents reported ADRs during their practice. A total of 93.8% of the respondents agreed that ADR reporting should be made mandatory for health-care professionals, and 94.5% agreed that it improves the patient safety. Conclusion: The findings generally indicate that health-care professionals in a tertiary care setting have low awareness regarding the term “ADR.” Lack of pharmacovigilance training, amount of workload, and legal liabilities are the main causes of underreporting. More than half of the respondents agreed that ADR reporting eventually improves patient safety