Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations  Joseph G. Verbalis, MD, Steven R. Goldsmith, MD, Arthur Greenberg, MD, Cynthia Korzelius, MD, Robert W. Schrier, MD, Richard H. Sterns, MD, Christopher J. Thompson, MD, FRCPI  The American Journal of Medicine  Volume 126, Issue 10, Pages S1-S42 (October 2013) DOI: 10.1016/j.amjmed.2013.07.006 Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 1 Risk of bone fracture in relation to serum [Na+] in patients with chronic kidney disease. Odds ratio (95% confidence interval) of fracture occurrence by serum [Na+] category, adjusting simultaneously for age (years), T-score, chronic kidney disease stage, osteoporotic risk factors (amenorrhea, low dietary calcium intake, high alcohol intake, maintenance steroids, ever having smoked, family history of osteoporosis, and history of liver disease), and osteoporosis therapy (use of calcium, vitamin D, antiresorptive therapy, and hormonal replacement therapy). Reproduced with the permission of the American Society of Nephrology, from Kinsella S, Moran S, Sullivan MO, et al. Clin J Am Soc Nephrol. 2010;5:275-280; permission conveyed through Copyright Clearance Center, Inc.31 The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 2 Mechanism of renal water reabsorption induced by arginine vasopressin (AVP) activation of the V2 receptor on renal collecting duct principal cells. AVP binds to the G-protein-linked V2 receptor on the basolateral membrane. G-protein-coupled receptor signaling consists of three steps: a hepta-helical receptor that detects a ligand (in this case, AVP) in the extracellular milieu, a G-protein (Gαs) that dissociates into α subunits bound to GTP and βγ subunits after interaction with the ligand-bound receptor, and an effector (adenylyl cyclase) that interacts with the dissociated G-protein subunits to generate second messengers. AVP activates adenylyl cyclase, increasing the intracellular concentration of cyclic adenosine monophosphate (cAMP). Protein kinase-A (PKA) is the target of the generated cAMP. The binding of cAMP to the regulatory subunits of PKA induces a conformational change, causing these subunits to dissociate from the catalytic subunits. These activated subunits (C) are anchored to an aquaporin-2 (AQP2)-containing endocytic vesicle via an A-kinase anchoring protein (AKAP). The local concentration and distribution of the cAMP gradient is limited by phosphodiesterases (PDE). Phosphorylation of the AQP2 water channels in the endocytic vesicles leads to movement of the vesicles toward the luminal membrane via microtubules and actin filaments with eventual fusion into the luminal membrane, thereby increasing the water permeability of this membrane. Water (H2O) is then reabsorbed from the urine in the collecting duct into the principal cells along osmotic gradients. When AVP is not bound to the V2 receptor, AQP2 water channels are retrieved by an endocytic process, and water permeability returns to its original low rate. AQP3 and AQP4 water channels are expressed constitutively at the basolateral membrane and allow intracellular water to exit into the blood of the vasa recta. In the presence of medullary hyperosmolality, water therefore moves across the principal cell and returns into the circulation. This process results in urinary concentration, or antidiuresis. In the presence of nonosmotic AVP stimulation, water is retained and hyponatremia can occur. Adapted with the permission of the American Society of Nephrology, from Bichet DG. J Am Soc Nephrol. 2006;17:920-922; permission conveyed through Copyright Clearance Center, Inc. The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 3 Recommendations for relowering of serum sodium concentration ([Na+]) to goals (green) for patients presenting with serum [Na+] <120 mmol/L who exceed the recommended limits of correction (red) in the first 24 hours. Abbreviations: L = liter; mmol = millimole; ODS = osmotic demyelination syndrome. The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

Figure 4 Estimated probability of the need for long-term treatment of hyponatremia depending on the underlying etiology of the syndrome of inappropriate antidiuretic hormone secretion. Abbreviations: HIV = human immunodeficiency virus; SIADH = syndrome of inappropriate antidiuretic hormone secretion; SSRI = selective serotonin-reuptake inhibitor. Adapted with permission from WB Saunders Elsevier, from Verbalis JG. Disorders of water balance. In Brenner and Rector's The Kidney, Vol 1, 9th ed, pp. 540-594, 2012.196 The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

The American Journal of Medicine 2013 126, S1-S42DOI: (10. 1016/j The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

The American Journal of Medicine 2013 126, S1-S42DOI: (10. 1016/j The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions

The American Journal of Medicine 2013 126, S1-S42DOI: (10. 1016/j The American Journal of Medicine 2013 126, S1-S42DOI: (10.1016/j.amjmed.2013.07.006) Copyright © 2013 Elsevier Inc. Terms and Conditions