risk factors for hyponatremia with treatment of nocturia Joseph G. Verbalis, MD Professor of Medicine Chief, Endocrinology and Metabolism Director, Georgetown-Howard Universities Center for Clinical and Translational Science Georgetown University Washington, DC USA

body fluid compartments water is the largest component of our body; the major determinant of body water is AVP-regulated water excretion by the kidneys

AVP stimulation and effects hyperosmolality, hypovolemia, angiotensin II baroreceptors, natriuretic peptides + – AVP V1a Receptors V2 Receptors vasoconstriction renal H2O reabsorption

AVP regulation of water reabsorption from renal tubular cells Collecting Duct Cell AQP3 AQP4 H2O Vasa recta Collecting duct AQP2 Exocytic Insertion cAMP ATP PKA Recycling vesicle Endocytic Retrieval GTP (Gs) AVP AVP V2 Receptor The role of vasopressin in fluid regulation has become a focus of increased attention subsequent to the recognition of the usefulness of other hormonal blockers involved in body fluid homeostasis such as catecholamines, aldosterone, and angiotensin II. The schematic in this slide shows the way in which AVP acts in the kidneys to regulate body water balance. AVP stimulation of V2 receptors, located in the basolateral membrane of the renal tubular cell, activates a Gs subtype of guanine nucleotide binding protein (GTP, guanosine triphosphate), which in turn activates adenylate cyclase. The result is an increased concentration of cyclic-3'-5'-adenosine monophosphate (cAMP), as well as activation of protein kinase A (PKA). PKA triggers the vesicles that contain aquaporin 2 (AQP2) to fuse with the luminal plasma membrane of the collecting tubule, thereby allowing water to enter the cell. Passive resorption of water through the basolateral membrane (AQP3 and 4) along osmotic gradients by way of other water channels into the vasa recta ultimately leads to water retention. H2O basolateral membrane apical membrane Mayinger B, Hensen J. Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene [review]. Exp Clin Endocrinol Diabetes. 1999;107:157-165.

maximal urine excretion rate (ml/h) plasma osmolality (mOsm/kg H2O) plasma AVP (pg/ml) 296 294 292 290 288 286 284 282 280 278 276 9 8 urine osmolality (mOsm/kg H2O) 7 maximal urine excretion rate (ml/h) thirst osmotic threshold 6 5 4 250 3 500 2 1000 1 300 AVP osmotic threshold 100

requirements for producing positive water balance hyponatremia: AVP V2R activation positive water balance Let’s examine the cellular mechanisms underlying the adaptations to hyponatremia

chronic hyponatremia model in rats solid diet + tap water liquid diet Verbalis & Drutarosky, Kidney Int 34:351-360 1988

hyponatremia age-associted risks Let’s examine the cellular mechanisms underlying the adaptations to hyponatremia

effects of aging on body fluid homeostasis body composition reduced ECF and plasma volume increased osmotic fluxes kidney decreased urine concentrating ability decreased ability to conserve sodium brain decreased thirst perception. increased vasopressin secretion

age-associated changes in body composition aging typically leads to a 5-10% decrease in total body water (Beck & Lavizzo-Mourey, Ann Int Med 107:768-9, 1987) plasma volume decreases as much as 21% relative to body weight and surface area compared to younger individuals (Davy & Seals, J Appl Physiol 76:2059-62, 1994) equivalent changes in body water are associated with greater fluxes of plasma osmolality in the elderly (Hodak & Verbalis, Endocrinol Metab Clinics NA 34:1031-1046, 2005)

elderly subjects develop greater degrees of hyperosmolality following 24h fluid deprivation Rolls & Phillips, Nutrition Reviews 48:137, 1990

effects of aging on body fluid homeostasis body composition reduced ECF and plasma volume increased osmotic fluxes kidney decreased urine concentrating ability decreased ability to conserve sodium brain decreased thirst perception. increased vasopressin secretion

Rowe JW. J Gerontol 31:155-63, 1976

variability in age-associated decline in renal function as assessed by creatinine clearance Lindeman et al. J Am Geriatr Soc 33:278, 1985

effects of aging on body fluid homeostasis body composition reduced ECF and plasma volume increased osmotic fluxes kidney decreased urine concentrating ability decreased ability to conserve sodium brain decreased thirst perception. increased vasopressin secretion

elderly subjects drink less following 24h fluid deprivation despite higher plasma osmolalities Phillips et al, Age and Aging 22:26-33, 1993

AVP responses are potentiated in the elderly Helderman et al., J Gerontol 33:39-47, 1978

hyponatremia: sex-associated risks Let’s examine the cellular mechanisms underlying the adaptations to hyponatremia

renal V2R expression is increased in female rats levels of V2R mRNA (top) and protein (bottom) in male versus female rat kidneys Liu et al. Am J Physiol 300:F433, 2011

female rats are more sensitive to lower doses of desmopressin urine osmolality (top) and volume (bottom) in response to graded infusions of desmopressin Liu et al. Am J Physiol 300:F433, 2011

enhanced sensitivity of human females to lower doses of desmopressin Juul et al. Am J Physiol 300:F1116, 2011

chracteristics of a high risk patient to develop hyponatremia on desmopressin elderly (>65) female low BMI (<22) eGFR <50 low solute diet likes to drink tea