Fluid Balance Homeostasis Research Articles

Copeptin as a diagnostic and prognostic biomarker in pediatric diseases.

Arginine vasopressin (AVP) plays a main role in maintaining the homeostasis of fluid balance and vascular tone and in regulating the endocrine stress response in response to osmotic, hemodynamic and stress stimuli. However, the difficulty in measuring AVP limits its clinical application. Copeptin, the C-terminal part of the AVP precursor, is released in an equimolar concentration mode with AVP from the pituitary but is more stable and simple to measure. Therefore, copeptin has emerged as a promising surrogate marker of AVP with excellent potential for the diagnosis, differentiation and prognosis of various diseases in recent decades. However, its application requires further validation, especially in the pediatric population. This review focuses on the clinical value of copeptin in different pediatric diseases and the prospects for its application as a potential biomarker.

Imaging and Interventions for Lymphatic and Lymphatic-related Disorders.

The lymphatic system is critical in fluid balance homeostasis. Yet, until recently, lymphatic imaging has been outside of mainstream medicine due to a lack of robust imaging and interventional options. However, during the last 20 years, both clinical lymphatic imaging and interventions have shown dramatic advancement. The key to imaging advancement has been the interstitial delivery of contrast agents through lymphatic-rich tissues. These techniques include intranodal lymphangiography and dynamic contrast-enhanced MR lymphangiography. These methods provide the ability to image and recognize lymphatic anatomy and pathologic conditions. Percutaneous thoracic duct catheterization and embolization became the first widely accepted interventional technique for the management of chyle leaks. Advances in interstitial lymphatic embolization, as well as liver and mesenteric lymphatic interventions, have broadened the scope of possible lymphatic interventions. Also, recent techniques of lymphatic decompression allow for the treatment of a variety of lymphatic disorders. Finally, immunologic studies of central lymphatic fluid reveal the potential of lymphatic interventions on immunity. These advances herald an exciting new chapter for lymphatic imaging and interventions in the coming years.

Effects of 1-year treatment with canagliflozin on body composition and total body water in patients with type 2 diabetes.

To characterize the long-term changes in body composition associated with sodium-glucose cotransporter-2 (SGLT2) inhibitors. In this multicentre, single-arm, open-label study, 107 patients with type 2 diabetes were treated with canagliflozin 100 mg, as add-on therapy, for 12 months. Body composition was measured with a body composition analyser (T-SCAN PLUS) using the impedance method to prospectively analyse changes in body components, including percentage of body fat, body fat mass, total body water, muscle mass and mineral mass. Estimated plasma volume (PV) was calculated using the Kaplan formula. Body weight showed a significant decrease from 1month to 12 months of treatment with canagliflozin, with a higher rate of decrease in body fat in body composition. A significant decrease in mineral mass was also observed, but its rate was low. Following treatment with canagliflozin, changes in total body water did not affect intracellular water, and a significant decrease in extracellular water, including plasma components, was observed early and was sustained up to 12 months. Protein mass, a component of muscle mass, was not affected, with only a slight decrease in water volume observed. Canagliflozin decreased extracellular fluid and PV in addition to decreasing fat in the body via calorie loss resulting from urinary glucose excretion. This study suggested that SGLT2 inhibitors might reduce body weight by regulating fat mass or water distribution in the body and might have cardiac and renal protective effects by resetting the homeostasis of fluid balance.

Sex Specific Effects of Salt Loading in Oxytocin Neurons From The Supraoptic Nucleus

Arginine Vasopressin (AVP) and oxytocin (OXY) contribute to body fluid balance homeostasis. Salt loading (2% NaCl for 7 days) increases both AVP and OXY release in rats. The chronic increase in AVP release is associated with a change in the sensitivity of AVP neurons in the supraoptic nucleus (SON) to GABA so that GABAA receptor activation becomes excitatory. It is not clear if a similar mechanism is associated with chronic OXY release in this model. Our hypothesis is that changes in chloride homeostasis associated with salt loading occur in OXY neurons. To test this hypothesis, we used a chloride imaging approach with a ratiometric chloride sensitive dye, ClopHensorN (Addgene #50758) combined with an AAV with an oxytocin specific promoter (pFBOT563, Addgene # 40864). Adult, intact, Sprague Dawley rats of both sexes were anesthetized with isoflurane (2-3%) and were bilaterally injected with the AAV2-pFBOT--ClophensorN virus directly into the SON. After a two-week recovery period, the animals were sacrificed and the brains were rapidly removed. The SON was dissected away from the brain and the cells were dissociated, plated on cover slips, and incubated for two hours. After incubation, recordings were taken using ratiometric live cell imaging on an inverted microscope. Selected neurons were sequentially excited at 445nm and 556nm and then emission data was collected between 500-550nm and 580-653nm respectively. After 40 cycles of 3-second recordings, muscimol (100nM), a GABAA receptor agonist was transiently applied to the cells and then allowed to wash off. Background fluorescence was subtracted. In cells from males, muscimol resulted in chloride influx in 50% of the OXY cells tested while chloride influx was observed in all OXY cells tested from females. The results suggest that salt loading may influence GABA responses of OXY neurons in males but not females.

Vasopressin and Copeptin in health and disease.

Arginine Vasopressin (AVP) and copeptin derive from the same precursor molecule. Due to the equimolar secretion, copeptin responds as rapidly as AVP to osmotic, hemodynamic and unspecific stress-related stimuli and both peptides show a very strong correlation. The physiological functions of AVP are homeostasis of fluid balance, vascular tonus and regulation of the endocrine stress response. In contrast, the exact function of copeptin remains unknown. Since copeptin, in contrast to AVP, can easily be measured with a sandwich immunoassay, its main function so far that it indirectly indicates the amount of AVP in the circulation. Copeptin has emerged as a useful measure in different diseases. On one hand, through its characteristics as a marker of stress, it provides a unique measure of the individual stress burden. As such, it is a prognostic marker in different acute diseases such as ischemic stroke or myocardial infarction. On the other side, it has emerged as a promising marker in the diagnosis of AVP-dependent fluid disorders. Copeptin reliably differentiates various entities of the polyuria polydipsia syndrome; baseline levels >20pmol/L without prior fluid deprivation identify patients with nephrogenic diabetes insipidus, whereas levels measured upon osmotic stimulation with hypertonic saline or upon non-osmotic stimulation with arginine differentiate primary polydipsia from central diabetes insipidus. In patients with hyponatremia, low levels of copeptin together with low urine osmolality identify patients with primary polydipsia, but copeptin levels overlap in all other causes of hyponatremia, limiting its diagnostic use in hyponatremia. Copeptin has also been put forward as predictive marker for autosomal dominant polycystic kidney disease and for diabetes mellitus, but more studies are needed to confirm these findings.

Bidirectional Crosstalk between Lymphatic Endothelial Cell and T Cell and Its Implications in Tumor Immunity.

Lymphatic vessels have been traditionally considered as passive transporters of fluid and lipids. However, it is apparent from recent literature that the function of lymphatic vessels is not only restricted to fluid balance homeostasis but also extends to regulation of immune cell trafficking, antigen presentation, tolerance, and immunity, all which may impact the progression of inflammatory responses and diseases such as cancer. The lymphatic system and the immune system are intimately connected, and there is emergent evidence for a crosstalk between T cell and lymphatic endothelial cell (LEC). This review describes how LECs in lymph nodes can affect multiple functional properties of T cells and the impact of these LEC-driven effects on adaptive immunity and, conversely, how T cells can modulate LEC growth. The significance of such crosstalk between T cells and LECs in cancer will also be discussed.

Arginine Vasopressin and Copeptin in Perinatology.

Arginine vasopressin (AVP) plays a major role in the homeostasis of fluid balance, vascular tonus, and the regulation of the endocrine stress response. The measurement of AVP levels is difficult due to its short half-life and laborious method of detection. Copeptin is a more stable peptide derived from the same precursor molecule, is released in an equimolar ratio to AVP, and has a very similar response to osmotic, hemodynamic, and stress-related stimuli. In fact, copeptin has been propagated as surrogate marker to indirectly determine circulating AVP concentrations in various conditions. Here, we present an overview of the current knowledge on AVP and copeptin in perinatology with a particular focus on the baby’s transition from placenta to lung breathing. We performed a systematic review of the literature on fetal stress hormone levels, including norepinephrine, cortisol, AVP, and copeptin, in regard to birth stress. Finally, diagnostic and therapeutic options for copeptin measurement and AVP functions are discussed.

Copeptin in the diagnosis of vasopressin-dependent disorders of fluid homeostasis.

Copeptin and arginine vasopressin (AVP) are derived from a common precursor molecule and have equimolar secretion and response to osmotic, haemodynamic and stress-related stimuli. Plasma concentrations of copeptin and AVP in relation to serum osmolality are highly correlated. The physiological functions of AVP with respect to homeostasis of fluid balance, vascular tonus and regulation of the endocrine stress response are well known, but the exact function of copeptin is undetermined. Quantification of AVP can be difficult, but copeptin is stable in plasma and can be easily measured with a sandwich immunoassay. For this reason, copeptin has emerged as a promising marker for the diagnosis of AVP-dependent fluid disorders. Copeptin measurements can enable differentiation between various conditions within the polyuria-polydipsia syndrome. In the absence of prior fluid deprivation, baseline copeptin levels >20 pmol/l identify patients with nephrogenic diabetes insipidus. Conversely, copeptin levels measured upon osmotic stimulation differentiate primary polydipsia from partial central diabetes insipidus. In patients with hyponatraemia, low levels of copeptin together with low urine osmolality identify patients with primary polydipsia, and the ratio of copeptin to urinary sodium can distinguish the syndrome of inappropriate antidiuretic hormone secretion from other AVP-dependent forms of hyponatraemia.

Effects of nitric oxide on magnocellular neurons of the supraoptic nucleus involve multiple mechanisms

Physiological evidence indicates that the supraoptic nucleus (SON) is an important region for integrating information related to homeostasis of body fluids. Located bilaterally to the optic chiasm, this nucleus is composed of magnocellular neurosecretory cells (MNCs) responsible for the synthesis and release of vasopressin and oxytocin to the neurohypophysis. At the cellular level, the control of vasopressin and oxytocin release is directly linked to the firing frequency of MNCs. In general, we can say that the excitability of these cells can be controlled via two distinct mechanisms: 1) the intrinsic membrane properties of the MNCs themselves and 2) synaptic input from circumventricular organs that contain osmosensitive neurons. It has also been demonstrated that MNCs are sensitive to osmotic stimuli in the physiological range. Therefore, the study of their intrinsic membrane properties became imperative to explain the osmosensitivity of MNCs. In addition to this, the discovery that several neurotransmitters and neuropeptides can modulate their electrical activity greatly increased our knowledge about the role played by the MNCs in fluid homeostasis. In particular, nitric oxide (NO) may be an important player in fluid balance homeostasis, because it has been demonstrated that the enzyme responsible for its production has an increased activity following a hypertonic stimulation of the system. At the cellular level, NO has been shown to change the electrical excitability of MNCs. Therefore, in this review, we focus on some important points concerning nitrergic modulation of the neuroendocrine system, particularly the effects of NO on the SON.

Kidney–lung cross-talk and acute kidney injury

There is a growing appreciation for the role that acute kidney injury (AKI) plays in the propagation of critical illness. In children, AKI is not only an independent predictor of morbidity and mortality, but is also associated with especially negative outcomes when concurrent with acute lung injury (ALI). Experimental data provide evidence that kidney-lung crosstalk occurs and can be bidirectionally deleterious, although details of the precise molecular mechanisms involved in the AKI-ALI interaction remain incomplete. Clinically, ALI, and the subsequent clinical interventions used to stabilize gas exchange, carry consequences for the homeostasis of kidney function. Meanwhile, AKI negatively affects lung physiology significantly by altering the homeostasis of fluid balance, acid-base balance, and vascular tone. Experimental AKI research supports an "endocrine" role for the kidney, triggering a cascade of extra-renal inflammatory responses affecting lung homeostasis. In this review, we will discuss the pathophysiology of kidney-lung crosstalk, the multiple pathways by which AKI affects kidney-lung homeostasis, and discuss how these phenomena may be unique in critically ill children. Understanding how AKI may affect a "balance of communication" that exists between the kidneys and the lungs is requisite when managing critically ill children, in whom imbalance is the norm.

Comparison of the efficacy of four viral vectors for transducing hypothalamic magnocellular neurosecretory neurons in the rat supraoptic nucleus

Since transgenes were first cloned into recombinant adenoviruses almost 30 years ago, a variety of viral vectors have become important tools in genetic research. Viruses adeptly transport genetic material into eukaryotic cells, and replacing all or part of the viral genome with genes of interest or silencing sequences creates a method of gene expression modulation in which the timing and location of manipulations can be specific. The hypothalamo-neurohypophyseal system (HNS), consisting of the paraventricular (PVN) and supraoptic (SON) nuclei in the hypothalamus, regulates fluid balance homeostasis and is highly plastic, yet tightly regulated by extracellular fluid (ECF) osmolality and volume. Its reversible plasticity and physiological relevance make it a good system for studying interactions between gene expression and physiology. Here, four viral vectors were compared for their ability to transduce magnocellular neurosecretory neurons (MNCs) of the SON in adult rats. The vectors included an adenovirus, a lentivirus (HIV) and two serotypes of adeno-associated viruses (AAV5 and AAV2). Though adenovirus and AAV2 vectors have previously been used to transduce SON neurons, HIV and AAV5 have not. All four vectors transduced MNCs, but the AAV vectors were the most effective, transducing large numbers of MNCs, with minimal or no glial transduction. The AAV vectors were injected using a convection enhanced delivery protocol to maximize dispersal through the tissue, resulting in the transduction of neurons throughout the anterior to posterior length of the SON (∼1.5mm). AAV5, but not AAV2, showed some selectivity for SON neurons relative to those in the surrounding hypothalamus.

Maintenance of Plasma Volume and Serum Sodium Concentration Despite Body Weight Loss in Ironman Triathletes

To examine the relationship between body weight, plasma volume, and serum sodium concentration ([Na]) during prolonged endurance exercise. Observational field study. 2000 South African Ironman Triathlon. 181 male triathletes competing in an Ironman triathlon. Body weight, plasma volume, and serum ([Na]) change from pre- to postrace. Significant body weight loss occurred (-4.9 +/- 1.7%; P < 0.0001), while both plasma volume (1.0 +/- 11.2%; P = 0.4: NS) and serum [Na] (0.6 +/- 2.4%; P < 0.001) increased from pre- to postrace. Blood volume (-0.6 +/- 6.6%) and red cell volume (-2.6 +/- 5.5%; P < 0.001) decreased in conjunction with the body weight loss. There was a strong correlation between blood and plasma volume change, both as a percentage, and absolute change in fluid volume (r = 0.9; P < 0.001). Body weight change was positively correlated with plasma volume change (r = -0.4; P < 0.001), but inversely correlated with serum [Na] change (r = -0.4; P < 0.001). Plasma volume change was not significantly correlated with serum [Na] change (r = 0.0; NS). Serum [Na] change was inversely correlated with both percentage of red cell volume change (r = -0.2; P < 0.05) and percentage body weight change (r = -0.4; P < 0.001). Plasma volume and serum [Na] were maintained in male Ironman triathletes, despite significant (5%) body weight loss during the course of the race. Body weight was not an accurate "absolute" surrogate of fluid balance homeostasis during prolonged endurance exercise. Clinicians should be warned against viewing these three regulatory parameters as interchangeable during an Ironman triathlon.

Activation of kidney-directed neurons in the lamina terminalis by alterations in body fluid balance.

This study was undertaken to determine if neurons in the lamina terminalis, previously identified as projecting to the kidney (35), were responsive to alterations in stimuli associated with fluid balance homeostasis. Neurons in the lamina terminalis projecting to the kidney were identified by the retrograde transynaptic transport of Bartha's strain of pseudorabies virus in anesthetized rats. Rats were also exposed to 24-h water deprivation, intravenous hypertonic saline, or intracerebroventricular ANG II. To determine if "kidney-directed" neurons were activated following each stimulus, brain sections that included the lamina terminalis were examined immunohistochemically for viral antigen and Fos protein. With the exception of ANG II in the subfornical organ, all regions of the lamina terminalis contained neurons that were significantly activated by water deprivation, hypertonic saline, and ANG II. These results provide evidence for a neural substrate, which may underpin some of the effects of hypertonic saline and ANG II on renal function thought to be mediated through the lamina terminalis.

Nitric Oxide Modulation of Supraoptic Oxytocin and Vasopressin Neurons Involves Potentiation of Gabaergic Synaptic Inputs.

P41 There is growing evidence that nitric oxide (NO) in the central nervous system functions as a local neuromodulator in water balance and osmotic regulation. However, the precise mechanisms by which these actions are mediated are still poorly understood. Neuronal nitric oxide synthase (nNOS) is abundantly expressed in the supraoptic (SON) and paraventricular (PVN) nuclei. nNOS expression is up-regulated in conditions known to stimulate oxytocin (OT) and vasopressin (VP) hormone release, such as salt loading and water deprivation. Since several studies have shown that NO mainly decreases the excitability of OT and VP neurons, NO may function as a local inhibitory feedback on activated SON neurons. In the present study we combined in vivo and in vitro electrophysiological studies to investigate whether NO-induced inhibition of SON neurons is mediated by activation of GABAergic inputs in the SON. In vivo retrodialysis of the NO-donor SNP into the SON inhibited the firing activity of both OT and VP neurons. This inhibition was largely blocked by retrodialysis of the GABA A receptor antagonist bicuculline. In order to understand the cellular mechanisms linking NO and GABAergic systems in the SON, in vitro patch clamp recordings of GABA A synaptic currents were obtained from immunochemically identified neurons in hypothalamic slices. The frequency and amplitude of miniature GABA A synaptic currents in both OT and VP neurons were significantly increased by SNP. These results suggest that NO inhibition of neuronal excitability of OT and VP neurons is largely mediated by pre- and postsynaptic potentiation of GABAergic synaptic activity in the SON. Thus, the proposed NO-GABAergic inhibitory feedback in the SON might constitute an important mechanism by which NO regulates osmotic and fluid balance homeostasis.

Functional identification of central pressor pathways originating in the subfornical organ

The functional projections from pressor sites in the subfornical organ (SFO) were identified using the 2-deoxyglucose (2-DG) autoradiographic method in urethane-anesthetized, sinoaortic-denervated rats. Autoradiographs of brain and spinal cord sections taken from rats whose SFO was continuously stimulated electrically for 45 min with stereotaxically placed monopolar electrodes (150 microA, 1.5-ms pulse duration, 15 Hz) following injection of tritiated 2-DG were compared with control rats that received intravenous infusions of pressor doses of phenylephrine to mimic the increase in arterial pressure observed during SFO stimulation. Comparisons were also made to autoradiographs from rats in which the ventral fornical commissure (CFV), just dorsal to the SFO, was electrically stimulated. The pressor responses during either electrical stimulation of the SFO or intravenous infusion of phenylephrine were similar in magnitude. On the other hand, stimulation of the CFV did not elicit a significant pressor response. Electrical stimulation of the SFO increased 2-DG uptake, in comparison to the phenylephrine-infused rats, in the nucleus triangularis, septofimbrial nucleus, lateral septal nucleus, nucleus accumbens, bed nucleus of the stria terminalis, dorsal and ventral nucleus medianus (median preoptic nucleus), paraventricular nucleus of the thalamus, hippocampus, supraoptic nucleus, suprachiasmatic nucleus, paraventricular nucleus of the hypothalamus, and the intermediolateral nucleus of and central autonomic area of the thoracic spinal cord. In contrast, in rats whose CFV was stimulated, these nuclei did not demonstrate changes in 2-DG uptake compared with control animals that received pressor doses of phenylephrine. These data have demonstrated some of the components of the neural circuitry likely involved in mediating the pressor responses to stimulation of the SFO and the corrective responses to activation of the SFO by disturbances to circulatory and fluid balance homeostasis.

Plasma prolactin during the body fluid and electrolyte changes of dehydration and sodium depletion in steers

The effect of dehydration and sodium depletion on plasma prolactin levels in steer calves is very different from the changes seen in the rat and possibly in man. Removal of drinking water was followed by progressive dehydration for 96 h during which time packed cell volume (PCV) increased from 39.9% to 44.7% and plasma osmolarity (pOsm) rose from 303.3 mOsm to 342.0 mOsm/1 with hypernatraemia. At the same time plasma prolactin (pPRL) was rapidly reduced from a basal value of 2.3 ng/ml to barely measurable amounts and remained low during dehydration. Restoration of ad lib drinking water was followed by rapid reduction of PCV and pOsm to sub-basal levels during which time the pPRL increased significantly to persist at 15 ng/ml. Sodium depletion was produced by continuous loss of sodium-rich saliva from unilateral fistulation of a parotid duct. During sodium deficiency PCV increased from 38.6% to 45.6% but pOsm fell significantly from 299.9 mOsm/1 to 286 mOsm/1 with hyponatraemia. As in dehydration, during sodium depletion pPRL was suppressed, and after 7 days was reduced from a basal level of 5.4 ng/ml to 0.5 ng/ml. The sodium depleted steers when given 0.3M NaHCO 3, which they consumed readily to restore sodium homeostasis, restored the deficiency gradually in 5 days when pPRL, pOsm and PCV all returned to basal levels without any ‘overshoot’ or hypersecretion of pPRL. Our findings indicate that extracellular fluid volume changes, not electrolyte content, affect pPRL. This is in agreement with results obtained in the rat, and possibly in man, but the fact that in the steer, the endogenous changes in prolactin level show a profound reduction provides an extreme example of species difference. The means whereby both divergent physiological processes of dehydration and sodium depletion generate stimuli which inhibit prolactin secretion and the relevance of this response in fluid balance homeostasis requires further research.