Hyponatremia and Inflammation: The Emerging Role of Interleukin-6 in Osmoregulation

Although hyponatremia is a recognized complication of several inflammatory diseases, its pathophysiology in this setting has remained elusive until recently. A growing body of evidence now points to an important role for interleukin-6 in the non-osmotic release of vasopressin. Here, we review this evidence by exploring the immuno-neuroendocrine pathways connecting interleukin-6 with vasopressin. The importance of these connections extends to several clinical scenarios of hyponatremia and inflammation, including hospital-acquired hyponatremia, postoperative hyponatremia, exercise-associated hyponatremia, and hyponatremia in the elderly. Besides insights in pathophysiology, the recognition of the propensity for antidiuresis during inflammation is also important with regard to monitoring patients and selecting the appropriate intravenous fluid regimen, for which recommendations are provided. Copyright © 2010 S. Karger AG, Basel Published online: December 22, 2010 Reinout M. Swart, MD PO Box 2040 NL–3000 CA Rotterdam (The Netherlands) Tel. +31 6 2428 7308 E-Mail reinoutswart @ hotmail.com © 2010 S. Karger AG, Basel 1660–2137/11/1182–0045$38.00/0 Accessible online at: www.karger.com/nep D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 5: 28 :1 6 A M Swart/Hoorn/Betjes/Zietse Nephron Physiol 2011;118:p45–p51 p46 the interactions are complex and multifactorial, there is mounting evidence for a key role of the cytokine interleukin-6 [6, 7] . Here, our aim is to review the current evidence for the relationship between inflammation and osmoregulation by providing a brief overview of the involved pathways. Subsequently, we discuss in which hyponatremic disorders these mechanisms are likely to play a role, including hyponatremia during inflammation, but also hospital-acquired hyponatremia, postoperative hyponatremia, exercise-associated hyponatremia, and hyponatremia in the elderly ( table 1 ). Normal Osmoregulation Under normal circumstances, water balance is tightly controlled, and minor changes in serum osmolality will affect the release of vasopressin, the major hormone involved in water homeostasis. Several brain areas are involved in sensing serum osmolality and translating this signal to the release of vasopressin. These areas include the supraoptic and paraventricular nuclei (SON, PVN), the subfornical organ (SFO), and the organum vasculosum of the lamina terminalis (OVLT). Osmosensitive neurons possess mechanosensitive cation channels, including those of the transient receptor potential vanilloid family, that help transduce the signal of increased osmolality (reduced cell stretch) to vasopressin release from the posterior pituitary into the circulation [8, 9] . In addition, hyperosmolarity induces thirst and the subsequent water intake also helps to lower serum osmolality. Vasopressin docks on its vasopressin-2 receptor in the renal collecting duct and stimulates a cyclic AMP-dependent cascade, that results in the insertion of preformed aquaporin-2 water channels into the apical plasma membrane [10] . The presence of aquaporin-2 allows for the transcellular movement of water, provided that there is an osmotic gradient. Water exits the principal cells through the constitutively expressed basolateral water channels aquaporin-3 and -4 [10] . Non-osmotic vasopressin release can be ‘appropriate’ (i.e., caused by hypovolemia or a low effective arterial blood volume) or ‘inappropriate’. Clinically, the ensuing syndrome is called the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [2] . SIADH is characterized by euvolemia and high urine sodium and osmolality in the absence of diuretic use, adrenal, thyroid or pituitary insufficiency, edematous disorders (heart failure, liver cirrhosis, nephrotic syndrome), and renal dysfunction [2] . Biology of Interleukin-6 During inflammation, several proinflammatory cytokines are secreted into the systemic circulation to initiate the so-called ‘acute phase response’, which is part of the innate immune system. The most important proinflammatory cytokines are tumor necrosis factor (TNF), interleukin (IL)-1 , and IL-6 [11] . When triggered by endotoxins, these cytokines are secreted by monocytes and macrophages in a cascade-like fashion ( fig. 1 ). TNFand IL-1 stimulate their own and each other’s secretion, and both promote the release of IL-6. Conversely, IL-6 inhibits the endotoxin-induced secretion of TNFand the endotoxinand TNF-induced secretion of IL-1 , which renders it also an anti-inflammatory cytokine. Because of this dual action, IL-6 plays a critical role in the control of the overall inflammatory response. The effects of circulating IL-6 are mediated through a cell surface heterodimeric receptor complex composed of a ligandbinding subunit, the IL-6 receptor (IL-6R), and a signaltransducing subunit called gp130 ( fig. 2 ). The binding of IL-6 to its receptor stimulates the association of the receptor with gp130 and gp130 dimerization [12] . The intracellular signaling pathways downstream from the IL6R and the gp130 complex include janus kinases and signal transducers and activators of transcription protein ( fig. 2 ) [13] . The expression of gp130 is ubiquitous while that of IL-6R is restricted to certain cell types. However, Table 1. C linical examples of hyponatremia and inflammation Clinical disorder Evidence Ref. Hyponatremia during infection Hyponatremia has been reported in several infections, including pneumonia, meningitis, and HIV 2 Hospital-acquired hyponatremia Development of hyponatremia coincided with a rise in CRP 32 Exercise-associated hyponatremia Increased vasopressin and IL-6 after exercise and trend towards correlation 7 Hyponatremia during ageing No direct evidence in humans, but ageing rats produce more vasopressin and IL-6 during inflammation 23 Postoperative hyponatremia Plasma vasopressin and IL-6 are both increased after surgery, but no studies have measured both 34–36 D ow nl oa de d by : 54 .7 0. 40 .1 1 10 /6 /2 01 7 5: 28 :1 6 A M Hyponatremia and Inflammation Nephron Physiol 2011;118:p45–p51 p47 complexes of IL-6 and soluble IL-6R can elicit responses from gp130-expressing cells that lack cell surface IL-6R, a mechanism known as trans-signaling. Cytokine-Induced Vasopressin Release The most commonly used model to study the immune response has been the intravenous or intraperitoneal injection of lipopolysaccharides (LPS), components of the outer membrane of Gram-negative bacteria. LPS injection induces inflammation and consequently leads to increased plasma concentrations of TNF , IL-1 and IL-6. The observation that LPS, TNF, IL-1 and IL-6 can independently or synergistically stimulate the hypothalamus-pituitary-adrenal axis was one of the first pieces of evidence for the existence of immuno-neuroendocrine pathways [14] . Besides the increased secretion of corticotrophin-releasing hormone by the hypothalamus and adrenocorticotropic hormone by the anterior pituitary, increased secretion of the posterior pituitary hormones vasopressin and oxytocin was also observed [15] . LPS-induced vasopressin release was shown to be independent of known stimuli, including serum osmolality, Monocytes and macrophages