Distribution of body water Functions of body water Daily water balance Plasma Osmolality Water metabolism Vasopressin Stimuli for vasopressin release Thirst Hypernatremia Approach to Hypernatremia

1. Physiology of water balance
and
Hypernatremic disorders
Dr Abdullah Ansari
SR Nephrology
SGPGI Lucknow

2. Distribution of body water

3. Distribution of body water
• Water constitutes approximately 55% to 65% of body weight
• It varies with
Age
Gender
Body fat
• Total body wateris distributed between the intracellular and extracellular
fluid compartments

5. Body water content
Body water content in percentage of a body weight is lowest in
1. Well built man
2. Fat woman
3. Well nourished child
4. Fat Man

6. An adult of 70 kg body

7. Distribution of TBW

8. Functions of body water

9. Functions of body water
• Involved in Biochemical reactions
• Water act as reactant in many hydrolytic reactions of metabolic
pathways
• Transporting media of body:
• Transportation of nutrients and waste metabolites through
aqueous media of blood and tissue floods
• Regulates body temperature

10. Functions of body water
• Water transports Hormones, Enzymes, and blood cells
• Water act as a solvent for Electrolytes and Non electrolytes
• Water Facilitates Digestion and promoting Elimination of ingested
food
• Water serve as a tissue Lubricant

11. Daily water balance

12. Source Water
intake
(ml/day)
Source Water
output
(ml/day)
Ingested
water
1400 Urine 1500
Water
content of
food
800
Skin
Respiratory
tract
500
400
Water of
oxidation
300 Stool 100
Total: 2500 Total: 2500

13. Plasma Osmolality

14. Electrolytes In Body Fluid Compartments
INTRACELLULAR EXTRACELLULAR
Potassium Sodium
Magnesium Chloride
Phosphorous Bicarbonate

15. Osmotic equivalence
• Both ICF & ECF have an equivalent osmotic pressure despite different solute
compositions
• Most biologic membranes are semipermeable (i.e. freely permeable to water but
not to all aqueous solutes)
• Water flows across membrane to compartment with higher solute concentration
 a steady state is reached  osmotic pressures have equalized

16. Osmolarity: The number of moles per liter of solution
Osmolality: The number of moles per kg of Solvent
 Osmolality is preferred for biological systems, because it is temperature independent

17. Plasma Osmolality
• Sodium and its associated ions make the largest contribution (90%) for
plasma Osmolality
• Osmolality is measured directly by Osmometer
• Osmometer is based on the depression of freezing point or vapor pressure
which is related to the number of free solute particles of that solution

18. Plasma Osmolality
• Plasma osmolality can be calculated
• Both methods produce comparable results (the value obtained using this
formula is within 1-2% of that obtained by direct osmometry)

19. Plasma osmolality vs tonicity
• Plasma osmolality is determined by all the particles dissolved in plasma
while
• Plasma tonicity, i.e. “effective osmolality” is limited to only those particles
that exert an osmotic effect
• The effective osmolality is the function of the relative solute permeability
properties of the membrane separating the two compartments
Urea contributes to plasma osmolality but does not confer tonicity because its
high permeability allows for rapid equilibration across plasma membranes

20. Effective vs ineffective solutes
Effective solutes
• Impermeable to cell membranes and
restricted to ECF compartment (e.g.
Na+, mannitol)
• They create osmotic pressure
gradients across cell membranes,
leading to the osmotic movement of
water
Ineffective solutes
• Freely permeable to cell membranes
(e.g., urea, ethanol, methanol)
• They do not create osmotic pressure
gradients across cell membranes and
are not associated with such water
shifts

21. Glucose as a unique solute
• At physiological conditions, glucose is taken up by cells via active transport
mechanisms and acts as an ineffective solute
• But, under conditions of impaired cellular uptake (e.g. insulin deficiency),
it becomes an effective extracellular solute

22. Water metabolism

23. Water homeostasis
Thirst
Kidneys
Arginine
vasopressin

25. Regulated vs unregulated water intake & excretion
Unregulated water intake
• The intrinsic water content of ingested foods
• Consumption of beverages for taste (eg tea),
social or habitual reasons (eg alcohol)
Regulated water intake
• Fluids consumed in response to a perceived
sensation of thirst
Unregulated water excretion
• Insensible water losses, from sweating,
respiration and gastro-intestinal losses
• The obligate amount of water that kidneys
must excrete to eliminate solutes generated
by body metabolism
Regulated water excretion
• Renal excretion of free water in excess of the
obligate amount necessary to excrete
metabolic solutes

26. The determinants of unregulated water loss
• The water loss from the skin and lungs depends dress, temperature,
humidity and exercise
• The rate of urine solute excretion, which cannot be reduced below a
minimal obligatory level required to excrete the solute load

27. The volume of urine
The volume of urine required depends on
• The solute load
• The degree of antidiuresis
 At basal level of urinary concentration (urine osmolality = 600 mOsm/kg), a typical solute load of
900 to 1200 mOsm/day, would require a total urine volume of 1.5 to 2.0 L for excretion
 At maximal antidiuresis (urine osmolality = 1200 mOsm/kg), the same solute load would require
a minimal obligatory urine output of only 0.75 to 1.0 L/day

28. Vasopressin

29. Structure and synthesis
• It is a 9–amino acid cyclic peptide
• Synthesized by the supraoptic and paraventricular
magnocellular nuclei in the hypothalamus
• The posterior pituitary “neurohypophysis” contains
the distal axons of magnocellular neurons
• AVP has a half-life of 15-20 minutes and is rapidly
metabolized in the liver and the kidney

30. Mechanism of Vasopressin Action
AVP binds three types of receptors coupled to G proteins:
The V2 receptor is primarily localized in CD and leads to an increase in water
permeability through aquaporin 2 transporters
V1a/V1 Vascular and hepatic
V1b/V3 Anterior pituitary and pancreatic islet
V2 Renal

31. Aquaporin transporters
AQP1: Constitutively expressed and not regulated by AVP
AQP2: AVP affects both short and long-term regulation

32. AVP regulation of AQP2
Short-term regulation:
The “shuttle hypothesis” involves insertion of water channels from subapical
vesicles into the luminal membrane
The rapid and reversible increase in CD water permeability
Long-term regulation:
It involves AVP-mediated increased transcription of AQP2 related genes
Occurs if AVP levels are elevated for >24 hours

33. Cellular mechanism of vasopressin action

34. Vasopressin and urea transporters
• AVP also stimulates urea transporters
in the inner medullary CD
• Urea reabsorption increases inner
medullary tonicity and driving force
for water reabsorption
Inner medullary CD

35. Stimuli for vasopressin release

36. The regulatory control of vasopressin release

37. Stimuli for Vasopressin release
AVP
Osmotic Non-osmotic
Hemodynamic Drinking Nausea Hypoglycemia RAAS Drugs

38. Osmotic stimuli
• It efficiently maintain osmolality within 1-2% despite wide fluctuation in water intake
• The osmoreceptive cells termed as the “organum vasculosum of the lamina terminalis”
are located in the anterior hypothalamus, near the circumventricular organ
The plasma osmotic pressure is the most important stimulus under physiologic
conditions

39. Vasopressin secretion in response to increases in plasma osmolality
• Below threshold  AVP secretion is suppressed
to low or undetectable levels
• Above threshold  AVP secretion increases in
direct proportion to plasma osmolality
• In general, each 1-mOsm/kg H2O increase in
plasma osmolality causes an increase in the
plasma AVP level, ranging from 0.4 to 1.0 pg/mL

40. Relationship of plasma osmolality, plasma vasopressin concentrations,
urine osmolality, and urine volume
• The renal response (i.e. urinary osmolality) is
linear to AVP levels from 0.5 to 5 pg/mL, after
which urinary osmolality is maximal
• Urine volume is inversely related to urine
osmolality
• Maximal antidiuresis is achieved after plasma
osmolality increases by 5 to 10 mOsm/kg H2O
(2−4%) above the threshold for AVP

41. The osmotic threshold
• The osmotic threshold for AVP secretion ranges from 280 to 290 mOsm/kg H2O
• Multiple factors can alter the sensitivity and/or set point of osmoregulation
Genetic influences, individual differences in osmoregulation
Acute changes in blood pressure, volume or both
Aging, increases osmosensitivity
Metabolic factors, such as Ca2+ levels and various drugs
Women have increased osmosensitivity, particularly during luteal phase of menstrual cycle

42. The pregnancy-associated resetting of osmoregulation
• The set point of the osmoregulatory system is reduced more during pregnancy
• The possible involvement of the placental hormone relaxin has been suggested
• Increased NO production by relaxin has been reported to increase vasodilation

43. Stimulation of osmoreceptor neurons
• Sodium and its anions, are the most potent solutes
to stimulate AVP secretion and thirst
• Certain sugars like mannitol and sucrose are equally
effective when infused intravenously
• In contrast, noneffective solutes like urea result in
little or no increase in AVP levels
The efflux of water and the resultant shrinkage of
osmoreceptor neuron activates a stretch-inactivated,
noncationic channel that initiates depolarization and
firing of the neuron

44. NONOSMOTIC REGULATION: Hemodynamic Stimuli
• Small reductions (5-10%)  only minimal effects on
plasma AVP levels
• Large reductions (20-30%)  exponential release of
hormone many times higher than required to
produce maximal antidiuresis
Hypovolemia is a potent stimulus for AVP secretion

45. Osmotic stimuli vs hemodynamic Stimuli
• Moderate hypovolemia modulates the gain of the
osmoregulatory responses
• The direct effects on thirst and AVP secretion
occurring only during more severe hypovolemia
The minimal effect of small changes in blood volume and
pressure on AVP secretion contrasts sharply with the
extraordinary sensitivity of the osmoregulatory system

46. Hemodynamic stimuli pathway
• “Baroreceptors” in the cardiac atria, aorta and carotid sinus
• Afferent nerve fibers  vagus and glossopharyngeal nerves
 the nuclei of tractus solitarius  postsynaptic pathways
to PVN and SON

47. NONOSMOTIC REGULATION: Drinking
• Drinking lowers plasma AVP before any appreciable decrease in plasma osmolality
• It occurs independently of the composition of fluid ingested
• Sensory afferents in the oropharynx  glossopharyngeal nerve

48. NONOSMOTIC REGULATION: Nausea
• The pathway mapped to the chemoreceptor zone in area postrema of brainstem
• It can be activated by a variety of drugs and conditions
 Apomorphine, morphine, nicotine and alcohol
 Vasovagal reactions, diabetic ketoacidosis, acute hypoxia and motion sickness
The sensation of nausea, with or without vomiting, is the most potent stimulus to
AVP secretion

49. Effect of nausea on vasopressin secretion
• The effect is instantaneous and extremely
potent, even when the nausea is transient
• Pretreatment with fluphenazine, haloperidol
or promethazine abolishes the response

50. NONOSMOTIC REGULATION: Hypoglycemia
• Acute hypoglycemia is a less potent but reasonably consistent stimulus
• 20% decreases in glucose are required to increase AVP levels significantly
• The triggering factor is likely intracellular deficiency of glucose or ATP
• The rise in plasma AVP is not sustained with persistent hypoglycemia

51. NONOSMOTIC REGULATION:
Renin-Angiotensin-Aldosterone System
• Ang II stimulates AVP secretion at the circumventricular subfornical organ, in the
third ventricle
• SFO neural pathways  SON and PVN  AVP secretion
• High level of plasma Ang II is required to stimulate AVP, may be active only under
pharmacologic conditions

52. NONOSMOTIC REGULATION: Drugs
Excitatory stimulants such as isoproterenol, nicotine, high doses of morphine
stimulate AVP secretion by lowering blood pressure and/or producing nausea
Vasopressor drugs such as norepinephrine inhibit AVP secretion indirectly by raising
the arterial pressure
In low doses, opioids including morphine, met-enkephalin and interact with the
magnocellular neurosecretory system at several levels to inhibit secretion of AVP
The well-known inhibitory effect of ethanol on AVP secretion may be mediated by
endogenous opiates

53. Drugs and Hormones That Affect Vasopressin Secretion
Stimulatory
• Acetylcholine
• Nicotine
• Apomorphine
• Morphine (high doses)
• Epinephrine
• Isoproterenol
• Histamine
• Bradykinin
• Prostaglandin
• β-Endorphin
• 2-Deoxyglucose
• Angiotensin II
Inhibitory
• Norepinephrine
• Fluphenazine
• Haloperidol
• Promethazine
• Opioid agonists
• Morphine (low doses)
• Ethanol
• Carbamazepine
• Muscimol
• Glucocorticoids
• Clonidine
• Phencyclidine

54. Thirst

55. Thirst
• The body’s defense mechanism to increase water consumption in response to
perceived deficits of body fluids
• True thirst must be distinguished from other determinants of fluid intake such as
taste, dietary preferences and social customs
Thirst can be defined as a consciously perceived desire for water

56. Thirst mechanism
Osmotic thirst:
• Stimulated by intracellular dehydration caused by increased osmolality of ECF
• Osmoreceptors located in the anterior hypothalamus
Hypovolemic thirst:
• Stimulated by intravascular hypovolemia caused by losses of ECF
• Activation of baroreceptors and circulating Ang II
Hypertonicity is clearly the most potent
The actual perception of thirst occurs in the anterior cingulate cortex and insular cortex,
which receive information from circumventricular organs via relay nuclei in the thalamus

57. Thirst mechanism

58. Osmotic thirst threshold
• An increase in plasma osmolality of 2-3% above basal levels produces a strong
desire to drink
• The “osmotic thirst threshold” averages approximately 295 mOsm/kg H2O
• This level is above the osmotic threshold for AVP release and approximates the
plasma osmolality at which maximal concentration of urine is normally achieved

59. The thirst osmoreceptors
• The thirst osmoreceptors located in the anteroventral hypothalamus and OVLT
• Ineffective plasma solutes such as urea and glucose are ineffective at stimulating
thirst, whereas effective solutes such as NaCl and mannitol can stimulate thirst
• A modest decline in plasma osmolality induces a sense of satiation

60. Hypovolemic thirst
• The threshold for producing hypovolemic thirst is significantly higher
• Sustained decreases in blood pressure or volume of at least 4-8% required
• The blunted sensitivity in humans represents an adaptation for the erect posture
of primates, which predisposes them to wider fluctuations in blood pressures

61. Anticipatory thirst
• The best studied example is the increase in drinking that a few hours at the end
of their awake period, which serves to maintain hydration during sleep period
• This may be mediated by vasopressin containing neurons in supra-chiasmatic
nucleus, the brain nucleus controlling diurnal rhythms
• SCN neurons  project to OVLT  excite thirst-activating neurons

62. Integration of vasopressin secretion and thirst
Under normal physiologic conditions
• The sensitive osmoregulatory system for AVP secretion maintains osmolality by
adjusting renal water excretion
• Stimulated thirst does not represent a major regulatory mechanism
• Unregulated fluid ingestion supplies adequate water in excess of true “need”

63. Integration of vasopressin secretion and thirst
When unregulated water intake can’t adequately supply body needs in presence of
plasma AVP levels sufficient to produce maximal antidiuresis
• Plasma osmolality rises to levels that stimulate thirst
• Thirst essentially represents a backup mechanism
• The advantage of freeing humans from frequent episodes of thirst

64. Integration of vasopressin secretion and thirst

65. Disorders of insufficient vasopressin or vasopressin
effect
• Disorders of insufficient AVP or AVP effect are associated with inadequate urine
concentration and increased urine output termed as “polyuria”
• Diabetes insipidus, is characterized by excretion of abnormally large volumes of
urine (diabetes) that is dilute (hypotonic) and devoid of taste from dissolved
solutes (insipid), in contrast to the hypertonic, sweet-tasting urine characteristic
of diabetes mellitus (from the Greek, meaning honey)

66. Disorders of insufficient vasopressin or vasopressin
effect
If thirst mechanisms are intact:
• Thirst is stimulated with compensatory increases in fluid intake (“polydipsia”)
• This maintains normal plasma osmolality and serum electrolyte concentrations
If thirst is impaired, or fluid intake is insufficient to compensate for the increased
urine excretion:
• Hyperosmolality and hypernatremia can result

67. Disorders of insufficient vasopressin or vasopressin
effect

68. Hypernatremia

69. Hypernatremia
• A state of total body water deficiency absolute or relative to total body Na+
• It can result from
1. Water loss (diabetes insipidus)
2. Hypotonic fluid loss (osmotic diarrhea)
3. Hypertonic fluid gain (Na+ containing fluids)
Hypernatremia is defined as an increase in plasma Na+ concentration >145 mEq/L

70. The renal concentrating mechanism
• The first defense mechanism against
water depletion and hyperosmolarity
• Hypernatremia results from disorders
of urine concentration

71. The importance of thirst
• Thirst is the most important defense mechanism in preventing hypernatremia
• Hypernatremia is seen primarily in patients who
• Can’t experience or respond to thirst normally due to impaired mental status
(older adult or critically ill patients)
• Require others to provide fluid intake (infants)
Individuals who are alert and have access to water should not develop hypernatremia

72. Development of hypernatremia

73. Hypernatremia and hyperosmolality

74. Hypernatremia and hyperosmolality

75. Cellular adaptation to hypernatremia
Hypernatremia increases ECF osmolality, causing water
efflux and cell shrinkage
The cells imports ionic osmolytes (Na+, K+ and Cl-) within
minutes, which are highly cytotoxic
The osmostress increases tonicity-responsive enhancer
binding protein (TonEBP), a transcriptional factor
TonEBP causes cellular accumulation of less toxic organic
osmolytes (mainly myoinositol, sorbitol, betaine, taurine)
These organic osmolytes increases cellular reactive oxygen
species and cytokines

77. Brain shrinkage by hypernatremia
• Brain shrinkage can cause vascular
tearing with cerebral bleeding,
subarachnoid hemorrhage, and
permanent neurologic damage or
death
• Brain shrinkage is countered by
the adaptive response

78. Signs and symptoms of hypernatremia
• Acute hypernatremia: nausea, vomiting, lethargy, irritability, restlessness,
weakness, may progress to seizures and coma
• Chronic hypernatremia: (>48 hours) less neurological signs and symptoms
because of brain adaptation

79. Mortality in hypernatremia
• Hypernatremia induces diverse effects in multiple organ systems
• Short-term mortality is approximately 50-60%
• Even mild hypernatremia has a 30-day mortality of >20%

81. Question 1:
Is the patient hypernatremia related to water deficit or gain of Na+ ???

82. Diagnostic Approach in Hypernatremia
U Na+ <20
U Na+ variable
U Na+ >20 U Na+ >20
Tachycardia,
orthostatic changes Edema
Polyuria
Polyuria

83. Question 1:
Is the patient hypernatremia related to water deficit or gain of Na+ ???
 Patient’s hypernatremia is likely related to water deficit

84. Polyuric disorders
Polyuric disorders can result from either
• Increase in Cosm: loop diuretics, renal salt wasting, vomiting (bicarbonaturia),
alkali administration, mannitol administration
• Increase in Cwater: excess ingestion of water (psychogenic polydipsia) or in
abnormalities of renal concentrating mechanism (Diabetes Insipidus)

86. Water deprivation test
Test procedure:
• Water intake is restricted till the patient loses 3-5%
of body weight or till 3 consecutive hourly urinary
osmolality values are within 10% of each other
• Caution to prevent excessively dehydration
• Aqueous vasopressin, 5 units given subcutaneously,
and urinary osmolality measured after 60 minutes

87. Interpretation of water deprivation test

88. Caution for baseline hypernatremia
• By definition, the patient with baseline hypernatremia is hypertonic, with
an adequate stimulus for AVP by the posterior pituitary
• Therefore, a water deprivation test is unnecessary in hypernatremia
• Water deprivation has the risk for worsening the hypernatremia

89. AVP and copeptin levels
• Measurement of circulating AVP by radioimmunoassay, or measurement of
copeptin levels, is preferred to the tedious water deprivation test
• Under basal conditions, AVP levels are unhelpful because there is a significant
overlap among the polyuric disorders
• Measurement after a water deprivation test is more useful

90. Copeptin is a 39 amino acid long peptide derived from C terminal of precursor protein of AVP

91. Copeptin measurement
• The levels of copeptin in the circulation correlate with those AVP
• Copeptin has advantages over AVP in terms of
ex vivo stability of the marker
the ease and speed of measurement

93. Hypernatremia management
The goals of management are:
1. Identification of the underlying cause(s)
2. Correction of volume disturbances
3. Correction of hypertonicity

94. Treatment of Hypernatremia

95. Question 2:
Calculate the water deficit for serum Na+ of 140 mEq/l…

96. Calculation of free water deficit

97. Question 2:
Calculate the water deficit for serum Na+ of 140 mEq/l…
42 x (168/140 - 1) = 8.4 l
 Add obligatory water output to the calculated infusate volume

98. Question 3:
What is the choice of fluid ???

100. Question 3:
What is the choice of fluid ???

101. Choice of fluid for correction
• The preferred route for administering fluids is the oral route or a feeding tube
• If neither is feasible, fluids should be given intravenously
• Hypotonic fluids include pure water, 5% dextrose and 0.45% sodium chloride
• The more hypotonic the infusate, the lower the infusion rate required
• Except in frank circulatory compromise, normal saline is unsuitable for managing
hypernatremia

102. Question 4:
How to estimate reduction in serum Na+ with correction ???

103. Hypernatremia correction
ECF tonicity decreases by hypotonic fluid administration
Water enters in the cell, creating a cell-swelling force
Excess osmolytes are expelled
Cells return to their normal state
Rapid correction (abrupt fall in ECF tonicity) can outpace this regulatory volume
decrease, causing cell swelling and irreversible damage

104. Hypernatremia correction
• Serum sodium should be slowly corrected at a maximal rate of 0.5 mEq/l per hr,
typically replacing the free water deficit over 48-72 hours
• The plasma Na+ should not be corrected by >10 mEq/l per day
• In acute cases ( <48 hours), it may be safe to correct at a rate of 1 mEq/l per hr,
because accumulated electrolytes are rapidly extruded from brain cells

106. Question 4:
How to estimate reduction in serum Na+ with correction ???
 The more hypotonic the infusate,
the lower the infusion rate required
• Estimated reduction in serum Na+ per liter of
0.45% NS = (77-168) / (42+1) = -2.12 mEq/l
• Total fluid required to correct 10 mEq/l over 24
hours = 10/2.12 = 4.72 l
• Rate of infusion = 4.72/24 = 0.197 l/hr = 197 ml/hr

107. Caution
• It must be emphasized that calculation of free water deficit is only an
estimate based on several assumptions
• It is important to frequently assess plasma sodium to assure that the rate
of correction is proceeding as planned

109. When is dialysis indicated in the treatment of
hypernatremia?
• Hypernatremia in the setting of volume overload (e.g. heart failure, renal
failure and pulmonary edema)
• Dialysis has advantages of quick removal of excess sodium and fluid
• Dialysis may be beneficial in management of acute severe hypernatremia
E.g. a patient with serum sodium levels near 200 will remain hypernatremic for 5 days, if
treated with conventionally with fluids, but with dialysis this period may be curtailed

110. Dialysis in the treatment of hypernatremia
• Intermittent hemodialysis machines can’t deliver dialysate sodium >155 mEq/L
• CRRT may be advantageous in renal failure and chronic, extreme hypernatremia
Changes in sodium are slower with CRRT due to lower delivered sodium dialysance
with low flow rates of dialysate/replacement fluids and/or lower blood flow rates

111. CRRT in the treatment of hypernatremia
Spiking of the Dialysate/Replacement Fluid [Na+] in CRRT
Controlling Sodium Change with CRRT by Applying Kinetic Principles
Administering a Hypertonic Infusion in a Separate Infusion Line

112. CRRT in the treatment of hypernatremia
Spiking of the Dialysate/Replacement Fluid [Na+] in CRRT
• The sodium concentration of CRRT solution bag can be increased by adding
hypertonic saline (23.4% hypertonic saline contains 4 mEq of sodium per mL)
• The sodium dialysance can be reduced to very low levels <50 mL/min as
needed

113. CRRT in the treatment of hypernatremia
Controlling Sodium Change with CRRT by Applying Kinetic
Principles
• Sodium and urea have similar dialyzer solute transfer characteristics as both
are non-protein bound small solutes, hence effective urea clearance may
estimate sodium dialysance
• Sodium kinetic equation may be used for the quantification of sodium change

114. CRRT in the treatment of hypernatremia
Administering a Hypertonic Infusion in a Separate Infusion Line
• Running a separate infusion of 3% saline into the return limb of the CRRT
circuit using standard 140 mEq/L dialysate or RF
• Post-filter saline infusion would contribute minimally to the overall clearance

116. For hypernatremia correction
Go slow……