Effects of Intravenous [Pyr1]Apelin-13 on Healthy Volunteers With Artificially Induced SIAD

Overview

Hyponatremia is a common electrolyte imbalance which often results from hormonal disregulation. The study aims to investigate whether the apelin hormone, which plays a role in regulating salt and water balance in the body, can be used to treat hyponatremia. The study will involve healthy volunteers who will be given a medication that causes their bodies to retain water, thus inducing a temporary hyponatremia state. The researchers will measure the volunteers' blood and urine electrolyte levels to see how these are influenced by apelin administration. As comparison, the same measurements will be done in volunteers dosed with placebo instead of apelin. The researchers believe that apelin may be able to help to correct hyponatremia by increasing urine output. If the study focused in the healthy volunteers population is successful, the investigators will assess the effect of apelin administration in patients with chronic hyponatremia. The study's hypothesis is that intravenous apelin will increase urinary excretion and sodium levels in healthy participants with artificially induced hyponatremia.

Hyponatremia (defined as plasma sodium levels \<135 mmol/l) is the most frequent electrolyte and fluid disturbance with a prevalence up to 30% in hospitalized patients. It is usually classified according to its duration, its biochemical findings (hypotonic/isotonic/hypertonic, mild/moderate/profound), its symptoms severity (mild/moderate/severe) and volume status (hypovolemic/euvolemic/hypervolemic). Chronic hyponatremia (defined as a duration \> 48 hours) is associated with longer hospital stays and higher hospital costs, increased mortality and morbidity, such as gait instability, falls, osteoporosis, fractures and attention deficit. Hyponatremia is recognized as a marker of poor prognosis in multiple diseases, but the extent of its causative role has not been quantified to date. There is increasing evidence that correcting hyponatremia could improve clinical outcome. The most common etiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD) which is also the main etiology of hyponatremia overall. SIAD is characterized by an imbalanced arginine vasopressin (AVP) secretion or an increased renal AVP sensitivity. This leads to free water retention, thereupon to extracellular volume expansion and a subsequent renal sodium loss resulting in hypotonic hyponatremia. Patients with SIAD are usually older adults with many comorbidities and polypharmacy making physiological studies difficult to interpret due to many possible confounders. To overcome this limitation, the investigators designed a protocol of artificial SIAD induction in healthy volunteers through administration of desmopressin and water loading.This model allowed us to develop the use of the SGLT2 inhibitors empagliflozin as a promising treatment option for SIAD. The apelin receptor is a g-protein coupled receptor whose structure resembles the angiotensin 2 type 1 receptor. It has two endogenous ligands apelin and elabela, whose different isoforms are present in different organs and are thought to work in an autocrine/paracrine manner. Apelin is, inter alia, expressed in the magnocellular neurons of the hypothalamic supraoptic and paraventricular nuclei together with AVP and oxytocin. Apelin has a broad spectrum of beneficial physiological effects and thus represents an attractive new target in many medical fields. For instance, it naturally displays vasodilatatory and inotropic effects and promotes glucose uptake and lipolysis. In salt and water homeostasis, apelin counteracts the effects of AVP by inhibiting central AVP release and AVP renal effect, as well as by antagonizing the vasoconstrictive effects of angiotensin II on renal afferent arterioles and increasing renal blood flow. AVP and apelin have been shown to change in opposite directions upon hypo- and hyperosmotic challenges in healthy humans. A cross-sectional study in hyponatremic patients with SIAD or heart failure suggests that not only an increased copeptin (surrogate stoichiometric marker of AVP) but also relative insufficient apelin levels contribute to renal water reabsorption in hyponatremia. Re-establishing a physiological copeptin apelin ratio by administering exogenous apelin could therefore restore a normal salt and water balance. This concept was tested in hyponatremic rats in which an apelin-17 analog increased urine output, decreased urine osmolality and increased sodium levels to a similar extent as tolvaptan. These results suggest that apelin could become an effective treatment for SIAD, once a long-acting analog will be developed for human use. However, whether a similar effect could be induced in humans is still not known and needs to be investigated in order to characterize apelin physiology in disorders of salt and water balance. The investigators therefore hypothesize, that the administration of intravenous \[Pyr1\]apelin-13, the most common apelin isoform in the blood, increases urinary excretion and thus sodium levels in healthy participants with artificially induced SIAD. In case the hypothesis is confirmed, the investigators aim to investigate the physiological effect of intravenous \[Pyr1\]apelin-13 administration in hyponatremic patients with chronic SIAD.