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Aldosterone, Inflammation, Immune System, and Hypertension.
Ferreira, NS, Tostes, RC, Paradis, P, Schiffrin, EL
American journal of hypertension. 2021;(1):15-27
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Abstract
Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress, and other manifestations of end-organ damage that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart, and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates proinflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome, and heart failure.
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Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians.
Nuñez-Gonzalez, L, Carrera, N, Garcia-Gonzalez, MA
International journal of molecular sciences. 2021;(21)
Abstract
Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.
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A Journey through the Early Evidence Linking Hydration to Metabolic Health.
Vanhaecke, T, Perrier, ET, Melander, O
Annals of nutrition & metabolism. 2020;:4-9
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Abstract
The idea that water intake or hydration may play an intrinsic, independent role in modulating metabolic disease risk is relatively recent. Here, we outline the journey from early experimental works to more recent evidence linking water and hydration to metabolic health. It has been known for decades that individuals with existing metabolic dysfunction experience challenges to body water balance and have elevated arginine vasopressin (AVP), a key hormone regulating body fluid homeostasis. Later, intervention studies demonstrated that altering fluid balance in these individuals could worsen their condition, suggesting that hydration played a role in modulating glycemic control. More recently, observational and interventional studies in healthy individuals have implicated the hydration-vasopressin axis in the pathophysiology of metabolic diseases. Individuals with higher AVP (or its surrogate, copeptin) are at higher risk for developing type 2 diabetes and components of the metabolic syndrome, an association that remains even when controlling for known risk factors. Supporting preclinical work also suggests a causal role for AVP in metabolic dysfunction. It is known that individuals who habitually drink less fluids tend to have higher circulating AVP, which may be lowered by increasing water intake. In the short term, water supplementation in habitual low drinkers with high copeptin may reduce fasting glucose or glucagon, generating a proof of concept for the role of water supplementation in reducing incident metabolic disease. A large randomized trial is ongoing to determine whether water supplementation for 1 year in subjects with low water intake can meaningfully reduce fasting glucose, risk of new-onset diabetes, and other cardiometabolic risk factors.
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Hydration Status and Cardiovascular Function.
Watso, JC, Farquhar, WB
Nutrients. 2019;(8)
Abstract
Hypohydration, defined as a state of low body water, increases thirst sensations, arginine vasopressin release, and elicits renin-angiotensin-aldosterone system activation to replenish intra- and extra-cellular fluid stores. Hypohydration impairs mental and physical performance, but new evidence suggests hypohydration may also have deleterious effects on cardiovascular health. This is alarming because cardiovascular disease is the leading cause of death in the United States. Observational studies have linked habitual low water intake with increased future risk for adverse cardiovascular events. While it is currently unclear how chronic reductions in water intake may predispose individuals to greater future risk for adverse cardiovascular events, there is evidence that acute hypohydration impairs vascular function and blood pressure (BP) regulation. Specifically, acute hypohydration may reduce endothelial function, increase sympathetic nervous system activity, and worsen orthostatic tolerance. Therefore, the purpose of this review is to present the currently available evidence linking acute hypohydration with altered vascular function and BP regulation.
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Myths and methodologies: Making sense of exercise mass and water balance.
Cheuvront, SN, Montain, SJ
Experimental physiology. 2017;(9):1047-1053
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Abstract
What is the topic of this review? There is a need to revisit the basic principles of exercise mass and water balance, the use of common equations and the practice of interpreting outcomes. What advances does it highlight? We propose use of the following equation as a way of simplifying exercise mass and water balance calculations in conditions where food is not consumed and waste is not excreted: ∆body mass - 0.20 g/kcal-1 = ∆body water. The relative efficacy of exercise drinking behaviours can be judged using the following equation: percentage dehydration = [(∆body mass - 0.20 g kcal-1 )/starting body mass] × 100. Changes in body mass occur because of flux in liquids, solids and gases. This knowledge is crucial for understanding metabolism, health and human water needs. In exercise science, corrections to observed changes in body mass to estimate water balance are inconsistently applied and often misinterpreted, particularly after prolonged exercise. Although acute body mass losses in response to exercise can represent a close surrogate for body water losses, the discordance between mass and water balance equivalence becomes increasingly inaccurate as more and more energy is expended. The purpose of this paper is briefly to clarify the roles that respiratory water loss, gas exchange and metabolic water production play in the correction of body mass changes for fluid balance determinations during prolonged exercise. Computations do not include waters of association with glycogen because any movement of water among body water compartments contributes nothing to water or mass flux from the body. Estimates of sweat loss from changes in body mass should adjust for non-sweat losses when possible. We propose use of the following equation as a way of simplifying the study of exercise mass and water balance: ∆body mass - 0.20 g kcal-1 = ∆body water. This equation directly controls for the influence of energy expenditure on body mass balance and the approximate offsetting equivalence of respiratory water loss and metabolic water production on body water balance. The relative efficacy of exercise drinking behaviours can be judged using the following equation: percentage dehydration = [(∆body mass - 0.20 g kcal-1 )/starting body mass] × 100.
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Intravenous fluids: balancing solutions.
Hoorn, EJ
Journal of nephrology. 2017;(4):485-492
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Abstract
The topic of intravenous (IV) fluids may be regarded as "reverse nephrology", because nephrologists usually treat to remove fluids rather than to infuse them. However, because nephrology is deeply rooted in fluid, electrolyte, and acid-base balance, IV fluids belong in the realm of our specialty. The field of IV fluid therapy is in motion due to the increasing use of balanced crystalloids, partly fueled by the advent of new solutions. This review aims to capture these recent developments by critically evaluating the current evidence base. It will review both indications and complications of IV fluid therapy, including the characteristics of the currently available solutions. It will also cover the use of IV fluids in specific settings such as kidney transplantation and pediatrics. Finally, this review will address the pathogenesis of saline-induced hyperchloremic acidosis, its potential effect on outcomes, and the question if this should lead to a definitive switch to balanced solutions.
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Optimizing the restoration and maintenance of fluid balance after exercise-induced dehydration.
Evans, GH, James, LJ, Shirreffs, SM, Maughan, RJ
Journal of applied physiology (Bethesda, Md. : 1985). 2017;(4):945-951
Abstract
Hypohydration, or a body water deficit, is a common occurrence in athletes and recreational exercisers following the completion of an exercise session. For those who will undertake a further exercise session that day, it is important to replace water losses to avoid beginning the next exercise session hypohydrated and the potential detrimental effects on performance that this may lead to. The aim of this review is to provide an overview of the research related to factors that may affect postexercise rehydration. Research in this area has focused on the volume of fluid to be ingested, the rate of fluid ingestion, and fluid composition. Volume replacement during recovery should exceed that lost during exercise to allow for ongoing water loss; however, ingestion of large volumes of plain water results in a prompt diuresis, effectively preventing longer-term maintenance of water balance. Addition of sodium to a rehydration solution is beneficial for maintenance of fluid balance due to its effect on extracellular fluid osmolality and volume. The addition of macronutrients such as carbohydrate and protein can promote maintenance of hydration by influencing absorption and distribution of ingested water, which in turn effects extracellular fluid osmolality and volume. Alcohol is commonly consumed in the postexercise period and may influence postexercise rehydration, as will the coingestion of food. Future research in this area should focus on providing information related to optimal rates of fluid ingestion, advisable solutions to ingest during different duration recovery periods, and confirmation of mechanistic explanations for the observations outlined.
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Osmolality and blood pressure stability during hemodialysis.
Singh, AT, Mc Causland, FR
Seminars in dialysis. 2017;(6):509-517
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Abstract
Homeostatic regulation of plasma osmolality (POsm) is critical for normal cellular function in humans. Arginine vasopressin (AVP) is the major hormone responsible for the maintenance of POsm and acts to promote renal water retention in conditions of increased POsm. However, AVP also exerts pressor effects, and its release can be stimulated by the development of effective arterial blood volume depletion. Patients with end-stage renal disease on hemodialysis, particularly those with minimal or no residual renal function, have impaired ability to regulate water retention in response to AVP. While hemodialysis can assist with this task, patients are subject to relatively rapid shifts in volume and electrolytes during the procedure. This can result in the development of transient osmotic gradients that lead to the movement of water from the extracellular to the intracellular space. Hypotension may result-both as a consequence of water movement out of the intravascular compartment, but also from impaired AVP release and inadequate vascular tone. In this review, we explore the evidence for POsm changes during hemodialysis, associations with adverse outcomes, and methods to minimize the rapidity of changes in POsm in an effort to reduce patient symptoms and minimize intra-dialytic hypotension.
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Non-steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease.
Bramlage, P, Swift, SL, Thoenes, M, Minguet, J, Ferrero, C, Schmieder, RE
European journal of heart failure. 2016;(1):28-37
Abstract
Pharmaceutical antagonism of the mineralocorticoid receptor (MR) can protect against organ damage caused by elevated aldosterone levels in patients experiencing heart failure (HF), chronic kidney disease (CKD), primary aldosteronism, and hypertension. While traditional steroid-based MR antagonists effectively reduce mortality rates and extend patient survival, their broad application has been limited by significant side effects, most notably hyperkalaemia. Recently, finerenone (BAY 94-8862) has emerged as a next-generation non-steroidal dihydropyridine-based MR antagonist designed to minimize off-target effects while maintaining potent efficacy. In this review, the outcomes of finerenone therapy in several diseases associated with MR activity are explored. The (pre-) clinical efficacy of finerenone is compared with that of traditional steroid-based MR antagonists. Finally, recent and ongoing clinical trials using finerenone to treat chronic HF, CKD, and diabetic nephropathy are discussed. Taken together, pre-clinical and clinical evidence suggests that finerenone may achieve equivalent organ-protective effects with reduced levels of electrolyte disturbance compared with traditional steroid-based MR antagonists. This supports further clinical development of finerenone for the treatment of cardiovascular and renal disease.
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Efficacy and Safety of Vasopressin Receptor Antagonists for Euvolemic or Hypervolemic Hyponatremia: A Meta-Analysis.
Zhang, X, Zhao, M, Du, W, Zu, D, Sun, Y, Xiang, R, Yang, J
Medicine. 2016;(15):e3310
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Abstract
Hyponatremia, defined as a nonartifactual serum sodium level <135 mmol/L, is the most common fluid and electrolyte abnormality in clinical practice. Traditional managements (fluid restriction, hypertonic saline and loop diuretics, etc.) are difficult to maintain or ineffective. Recently, vasopressin receptor antagonists (VRAs) have shown promise for the treatment of hyponatremia. We aimed to conduct a meta-analysis to evaluate the efficacy and safety of VRAs in patients with euvolemic or hypervolemic hyponatremia. We searched Pubmed, Cochrane Library, Web of Science and Springer, etc. (latest search on June 4, 2015) for English publications with randomized controlled trials. Two authors independently screened the citations and extracted data. We calculated pooled relative risk (RR), risk difference (RD), weighted mean difference (WMD) or standard mean difference (SMD), and 95% confidence intervals (CIs) by using random and fixed effect models. We collected data from 18 trials involving 1806 patients. Both random and fixed effect meta-analyses showed that VRAs significantly increased the net change of serum sodium concentration (WMD(random) = 4.89 mEq/L, 95%CIs = 4.35-5.43 and WMD(fixed) = 4.70 mEq/L, 95%CIs = 4.45-4.95), response rate (RR(random )= 2.77, 95%CIs = 2.29-3.36 and RR(fixed) = 2.95, 95%CIs = 2.56-3.41), and 24-hour urine output (SMD(random) = 0.82, 95%CIs = 0.65-1.00 and SMD(fixed) = 0.79, 95%CIs = 0.66-0.93) compared to placebo. Furthermore, VRAs significantly decreased body weight (WMD(random) = -0.87 kg, 95%CIs = -1.24 to -0.49 and WMD(fixed) = -0.91 kg, 95%CIs = -1.22 to -0.59). In terms of safety, rates of drug-related adverse events (AEs), rapid sodium level correction, constipation, dry mouth, thirst, and phlebitis in the VRA-treated group were greater than those in control group. However, there was no difference in the total number of AEs, discontinuations due to AEs, serious AEs, death, headache, hypotension, nausea, anemia, hypernatremia, urinary tract infection, renal failure, pyrexia, upper gastrointestinal bleeding, diarrhea, vomiting, peripheral edema, and dizziness between the 2 groups. Random effect meta-analyses showed that post treatment urine osmolality, supine systolic blood pressure, and diastolic blood pressure were lowered (WMD(random) = -233.07 mOsmol/kg, 95%CIs = -298.20-147.94; WMD(random) = -6.11 mmHg, 95%CIs = -9.810 to -2.41; WMD(random )= -2.59 mmHg, 95%CIs = -4.06 to -1.11, respectively), but serum osmolality was increased (WMD(random) = 9.29 mOsmol/kg, 95%CIs = 5.56-13.03). There was no significant change from baseline in serum potassium concentration between the 2 groups (WMD(fixed) = 0.00 mmHg, 95%CIs = -0.07-0.06). VRAs are relatively effective and safe for the treatment of hypervolemic and euvolemic hyponatremia.