1. 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

2. 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

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

4. 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:

5. 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

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

7. chronic hyponatremia model in rats
solid diet + tap water
liquid diet
Verbalis & Drutarosky, Kidney Int 34:

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

9. 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

10. 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: , 1994)
equivalent changes in body water are associated with greater fluxes of plasma osmolality in the elderly (Hodak & Verbalis, Endocrinol Metab Clinics NA 34: , 2005)

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

12. 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

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

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

15. 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

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

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

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

19. 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

20. 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

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

22. 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