The Syndrome of Inappropriate Antidiuresis: Pathophysiology, Clinical Management and New Therapeutic Options

Hyponatremia is a marker of different underlying diseases and it can be a cause of morbidity itself; this implies the importance of a correct approach to the problem. The syndrome of inappropriate antidiuresis (SIAD) is one of the most common causes of hyponatremia: it is a disorder of sodium and water balance characterized by urinary dilution impairment and hypotonic hyponatremia, in the absence of renal disease or any identifiable non-osmotic stimulus able to induce antidiuretic hormone (ADH) release; according to its definition, it is diagnosed through an exclusion algorithm. SIAD is usually observed in hospitalized patients and its prevalence may be as high as 35%. The understanding of the syndrome has notably evolved over the last years, as reflected by the significant change in the name, once the syndrome of inappropriate secretion of ADH (SIADH), today SIAD. This review is up to date and it analyses the newest notions about pathophysiological mechanisms, classification, management and therapy of SIAD, including vaptans. Copyright © 2011 S. Karger AG, Basel Published online: June 15, 2011 Pasquale Esposito Department of Nephrology Dialysis and Transplantation, Fondazione Policlinico S.Matteo Piazzale Golgi 2, IT–27100 Pavia (Italy) Tel. +39 038 250 3883, E-Mail pasqualeesposito @ hotmail.com © 2011 S. Karger AG, Basel 1660–2110/11/1191–0062$38.00/0 Accessible online at: www.karger.com/nec D ow nl oa de d by : 54 .1 91 .4 0. 80 9 /1 6/ 20 17 8 :5 1: 03 P M SIAD: New Concepts and Treatments Nephron Clin Pract 2011;119:c62–c73 c63 tricular nuclei neurons, then transported along the axons to the posterior lobe of the hypophysis and, in response to a number of stimuli, is released into the circulation [3] . Circulating ADH is rapidly metabolized by hepatic and renal aminopeptidase with a half-time in humans of about 18 min. In particular, vasopressinase, also called oxytocinase or placental leucine aminopeptidase, is a widely expressed type II membrane-spanning protein of the M1 aminopeptidase family, which cleaves S-benzyl-cysteine and inactivates vasopressin (and oxytocin) by releasing its N-terminal cysteine residues. It is expressed as a membrane protein and then secreted into the blood through proteolytic cleavage [4] . The circulating form of vasopressinase could be an important regulator of ADH levels and it is particularly abundant during pregnancy, insomuch as its elevated levels have been proposed as the main cause of gestational diabetes insipidus [5] . Three known receptors bind ADH at the cell membrane: V1a, V1b (also known as V3) and V2. These receptors belong to the G-protein-coupled receptor superfamily. ADH binding to V1a and V1b receptors results in phospholipase C activation and elevation of intracellular calcium that, in turn, stimulates protein kinase C. Instead, the binding to V2 receptors activates adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate (cAMP) [6] . V1a subtype is ubiquitous and it is found on several cells, such as vascular smooth muscle cells, hepatocytes, platelets, brain and uterus cells. This receptor mediates the cardiovascular effects of ADH, which exerts its hypertensive effects mainly through smooth muscle cell contraction [7] . Moreover, the stimulation of V1a receptors regulates glycogenolysis, platelet aggregation, myocyte hypertrophy, anxiety and stress [8] . V1b receptors are found predominantly in the anterior pituitary gland and their stimulation results in the release of adrenocorticotropic hormone (ACTH) [9] . Finally, V2 receptors are found in endothelial cells, where their activation induces the secretion of von Willebrand factor [8] , and on the basolateral membrane of the principal cells of the renal collecting ducts, where they mediate an antidiuretic response. Stimulation of V2 receptors, through intracellular cAMP, increases synthesis and insertion of aquaporin-2 (AQP2) water channels in the luminal membrane of the collecting ducts, thus making them permeable to water [10] . Consequently, water passes passively to the hypertonic interstitium of renal pyramids, resulting in urine concentration. ADH antidiuretic action also depends on its ability of maintaining the medullary interstitial osmotic gradients by increasing the number of epithelial [Na+] channels (ENaC) and urea transporters (UT-A1), thus enhancing sodium and urea permeability in the collecting duct [11] . ADH secretion is influenced by many different stimuli, which can be classified as osmotic and non-osmotic. Under physiological conditions, the most important stimulus is the effective osmotic pressure of plasma. Osmoreceptors are located in the anterior hypothalamus, outside the hemato-encephalic barrier, mostly on the vascular side of the terminal lamina around the ventricles, exposed to the osmotic variations of the systemic circulation [12] . The threshold for ADH release cessation corresponds to a plasmatic osmolality ! 275 mosm/kg, while for plasmatic osmolality of 284 mosm/kg or higher, ADH concentration rises linearly. ADH receptors are so sensitive that 1% osmotic variations are sufficient to determine significant modifications in ADH secretion [13] . Hypovolemia is a potent non-osmotic stimulus for ADH secretion in humans. Baroreceptors are classified in lowand high-pressure receptors and the activation of both of them results in ADH increase. The low-pressure receptors are located in larger veins, right and left atrium and lungs, while the high-pressure ones in the carotid sinuses and aortic arch. ECF depletion initially induces secretion of vasopressin through low-pressure receptors pathways, thus working even with normal arterial pressure [14] . Angiotensin II and norepinephrine, which reinforce the response to hypovolemia, further stimulate ADH secretion [15] . Among the other non-osmotic stimuli, like stress, nausea, vomiting, drugs and hypoglycemia [16] , nociceptive stimuli, mainly post-surgery pain, have been clearly associated with an increase in ADH levels, but the underlying mechanism has not been characterized so far [17] .