Overview of the pathophysiology or water, sodium and potassium metabolism and the medical management

1. Dr Alan Richardson
26 April 2013

2. Learning Objectives
 Logically investigate the causes of high and low levels
of electrolytes through case study review
 Compare and contrast the principles of vapour
pressure and freezing point osmometry
 Evaluate the use of the water deprivation test in the
investigation of diabetes insipidus

3. Total Body Water
 50-70% of body weight is water (lower in females,
higher in males) – about 42L
 2/3rds is intracellular (about 28L)
 Remaining 14L is spread between interstitial
compartments (3/4), plasma compartments and
transcellular compartments

4. Vander’s Renal Physiology. Eaton and
Pooler 6th Ed 2004
*

5. Body Fluid Compartments
 How do we work out total body water and its
distribution?
 TBW – deuterated or tritiated water
 ECF – sucrose, mannitol, inulin
 Plasma – 131I-albumin, 31Cr-erythrocytes
 Interstitial – ECW – plasma
 Intracellular – TBW - ECW
*

6. Changes to ECF volume
 Decreased
 Acute blood loss
 Vomiting and diarrhoea
 Diuretics
 Salt wasting diseases of renal or adrenal origin
 Increased
 Congestive heart failure
 Hepatic cirrhosis
 Nephrotic syndrome
 Iatrogenic

7. Third Space Losses
 Loss of volume to compartments of the body at the
expense of intravascular volume
 This can include interstitial and transcellular
compartments
 Bowel obstruction
 Peritonitis
 Pancreatitis
 Burns
 Sepsis
 Multitrauma
*

8. Vander’s Renal Physiology. Eaton and
Pooler 6th Ed 2004

9. Osmolality
 What is osmolality?
 Osmolality is a measure of the number of dissolved
particles per kg of water
 Essentially a measure of the osmotic pressure exerted
by a solution
 How do we measure it?
*

10. Freezing Point Depression
 Solution supercooled
below its freezing point
with gentle stirring
 Rapid stirring or vibration
initiated to start freezing
process
 Heat of fusion warms the
solution
 Freezing completes
*
http://www.iupui.edu/~cletcrse/380/ch3suppos.htm

11. Loser Messtechnik Osmometers
product application website.
Accessed 12/04/13

12. Vapour Pressure Depression
 Change in vapour pressure measured indirectly
through a decrease in dew point
 Sample placed in a vaporisation/condensation
chamber
 Temperature is then manipulated to establish thermal
and vapour equilibrium
 Cooling of the sample then occurs to below the dew
point of the sample causing condensation to occur
 This increases the temperature of the sample until the
dew point is achieved
*

13. ©Wescor Biomedical Systems. Accessed
from
http://panza.uchicago.edu/Phys.261/mat
erials/Osmometer/ on the 12/04/13

14. Vapour Pressure Depression
 Relies on the vapour released by a liquid condensing
again as the temperature is manipulated within a
narrow range
 Thus volatiles within a sample will easily become
gaseous but will not condense again at the
temperatures we are using
 Volatiles include ethanol, methanol, ethylene glycol
and even dissolved CO2

15. Calculated osmolality
Osm(calc) = 1.86 (Na+) + Glu + Urea + 9
 Osmolal gap (measured – calculated)
 Alcohols – methanol, ethanol, ethylene glycol
 Sugars – mannitol, sorbitol
 Ketoacidosis, lactic acidosis
 Lipids – hypertriglyceridaemia
 Proteins – multiple myeloma, Waldentrom’s
macroglobulinaemia
Dorwart and Chalmers Clin Chem 1975 21:190-194
*

16. Sodium and Water
 Water balance in adults
 Intake
 Oral fluid 1200ml
 Dietary 1000ml
 Metabolism 300ml 2500ml
 Output
 Insensible 700ml
 Sweat 100ml
 Faeces 200ml
 Urine 1500ml 2500ml

17. Sodium and Water
 Total body sodium
 70kg human contains about 4200 mmol of sodium
 50% in ECF
 40% in bones
 10% in ICF
 Abnormal plasma sodium concentrations are most
usually related to an abnormality in water balance,
rather than a primary abnormality in sodium balance

18. Sodium and Water
 Water balance is maintained primarily by sensation of
thirst (intake) and production of anti-diuretic
hormone (output)
 Control of ADH (vasopressin) is through two primary
triggers
 Osmolality
 Blood pressure
 Other less important factors include nausea, atrial
natriuretic peptide and angiotensin II
 Drugs including nicotine (stimulates) and ethanol
(inhibits) also affect its release

19. Sodium and Water
 Osmotic control of ADH secretion
 Changes in plasma osmolality are sensed by
osmoreceptor cells in the hypothalamus which respond
by either swelling or shrinking
 Osmoreceptor cells do not respond to all molecules
equally (respond well to changes in sodium, do not
respond at all to changes in urea)
 ADH has a half-life of 15-20 minutes so is rapidly broken
down when secreted
*

20. *
Physiology. Berne et al.5th Ed 2004

21. Sodium and Water
 Haemodynamic control of ADH secretion
 Baroreceptors located both in the high pressure
circulation (aortic arch and carotid sinus) and the low
pressure circulation (left atrium and large pulmonary
vessels)
 Signals sent by Vagus and Glossopharyngeal nerves to
the brain stem which then relays the signal to the
hypothalamic neuroendocrine cells
 Signals from these baroreceptors change both the set
point and the sensitivity of the neuroendocrine cells to
osmoreceptors
*

22. Physiology. Berne et al.5th Ed 2004
*

23. Principles of Anatomy and Physiology.
Tortora and Grabowski. 9th Ed 2000
*

24. Sodium and Water
 Actions of ADH
 Primary action is to increase the permeability of the
renal collecting ducts to water (and the medullary
portion of the collecting duct to urea)
 Acts via a G-protein coupled receptor to cause
intracellular vesicles containing specific water channels
(aquaporin type 2) to fuse with the apical cell membrane
(basolateral membranes are freely permeable to water)
 Also has the long term effect of altering the expression
of the aquaporin 2 gene

25. http://www.studyblue.com/#flashc
ard/view/1161375 accessed 12/04/13

26. Sodium and Water
 Thirst
 Perception of thirst initiated by changes in plasma osmolality,
blood volume and arterial pressure
 Hyperosmolality is more potent (2-3% increase in osmolality)
than a decrease in blood volume (10-15% decrease)
 Thirst centre is located in the hypothalamus
 Angiotensin II also acts on the hypothalamus to evoke a
sensation of thirst
 Sensors in the oropharynx and upper GIT detect the ingestion
of liquid and temporarily decrease the thirst impulse
*

27. Syndrome of Inappropriate ADH
 Continued ADH secretion in the presence of decreased plasma
osmolality causing the body to retain water inappropriately
 Causes a euvolaemic hyponatraemia and an inappropriately
concentrated urine
 Aetiology
 CNS pathology – infections, stroke, tumours, trauma, Guillain-
Barre Syndrome
 Lung disease – infections, cystic fibrosis, tuberculosis
 Malignancy – SCLC, oropharynx, GI tumours
 Drugs – antiepileptics, anticonvulsants, antipsychotics, MDMA
 Transient – nausea, pain, stress (HOSPITAL PATIENTS!)
 Hereditary – 4 different types of ADH problems - A (high ADH),
B (high basal ADH), C (low setpoint) and D (active receptor)
*

28. Diabetes Insipidus
 Inadequate effect of ADH results in the excretion of
large volumes of dilute urine (polyuria) which causes
the individual to consume large quantities of fluid
(polydipsia)
 Several forms
 Neurogenic – decreased ADH production
 Causes - hypothalamic or pituitary stalk lesion, idiopathic and
inherited forms
 Nephrogenic – defect in the renal receptor causing
decreased response to ADH
 Causes – genetic defects, metabolic abnormalities, drugs,
heavy metals, chronic kidney disease
*

29. Water Deprivation Test
 Used to investigate a patient with polyuria and polydipsia
to determine if the cause is psychogenic (primary)
polydipsia, neurogenic DI or nephrogenic DI
 Check thyroid, adrenal function and ensure K+ and Ca2+ are
normal
 Patient deprived of fluid for up to 8 hours and the
following parameters are measured
 Body weight
 Urine output
 Serum and Urine osmolality

30. Water Deprivation Test
Diagnosis Fluid deprivation Desmopressin
Primary polydipsia >600 >600
Neurogenic DI <300 >50% increase
Nephrogenic DI <300 <300
Primary polydipsia – low plasma osmolality at the start of
the test and will concentrate their urine appropriately during
water deprivation
Diabetes insipidus – confirmed by a plasma osmolality of
>300 and a urine osmolality of <300
*

31. *
Accessed 12/04/12 at
http://upload.wikimedia.org/wikipedia/commons/a/
a2/Renin-angiotensin-aldosterone_system.png

32. Hyponatraemia
 Normal plasma sodium is 135-145 mmol/L
 By definition, any plasma sodium value below 135
mmol/L is considered to constitute hyponatraemia
 Severity
 Mild 130-135 mmol/L
 Moderate 125-130 mmol/L
 Severe <125 mmol/L
*

33. Hyponatraemia
 Clinical presentation
 No symptoms
 Lethargy, fatigue
 Loss of appetite
 Restlessness and irritability
 Muscle weakness
 Neurological symptoms (hyponatraemic
encephalopathy)
 Headache, nausea, vomiting, confusion
 Seizures, cardiac and/or respiratory arrest
 Coma
*

34. Hyponatraemia
 Mrs YR is a 78 yr old female who presented blurred
vision but on further questioning admitted to a 2
month history of weakness, anorexia and weight loss.
Analyte Result Analyte Result
Na 119 (↓↓↓) TP 118 (↑↑↑)
K 5.7 (↑) Alb 24 (↓)
Cl 87 (↓) TBil 18
HCO3
- 23 ALP 97
Urea 17.2 (↑) GGT 44
Creat 197 (↑) AST 40

35. Hyponatraemia
 Pseudohyponatraemia
 In normal plasma 93% of the sample is water and the
rest is solute
 In patients with significant increases in proteins or
lipids there is a decrease in the percentage of the sample
that is water
 Direct ISEs measure correctly but indirect methods are
misled by the increased proportion of the sample that is
dissolved solid rather than water

36. [Na+
] 140 mmol/L
7% dissolved solids
(protein or lipids)
[Na+
] 140 mmol/L
22% dissolved solids
(protein or lipids)
Measured [Na+
]
= 119 mmol/L
Richardson A 2013

37. Hyponatraemia
 Hyperglycaemia
 Glucose in the serum is osmotically active and when it
accumulates to very high levels has two effects
 Osmotic diuresis – which results in a loss of water (with a
smaller sodium loss)
 Shift of water from ICF to ECF
 Rule of thumb: For every 3.5 mmol/L of glucose in the serum,
the serum sodium decreases by 1 mmol/L
 i.e. blood glucose of 70 mmol/L means that a sodium of 120
mmol/L is actually normal and will self correct when the
glucose is controlled
*

38. Hyponatraemia
 Classification based on ECF volume
 Hypovolaemic hyponatraemia
 Euvolaemic hyponatraemia
 Hypervolemic hyponatraemia

39. Hyponatraemia
 Hypovolemic hyponatraemia
 Renal sodium loss
 Diuretics
 Osmotic diuresis
 Adrenal insufficiency
 Renal tubular acidosis
 Extra-renal sodium loss
 Diarrhoea/vomiting
 Excessive sweating
 Third space sequestration
*

40. Hyponatraemia
 Euvolemic hyponatraemia
 Thiazide diuretics
 Hypothyroidism
 Adrenal insufficiency
 SIADH
 Decreased salt intake
 Beer potomania
 Tea and toast diet
 Psychogenic (primary) polydipsia
*

41. Hyponatraemia
 Hypervolemic hyponatraemia
 Congestive heart failure
 Hepatic cirrhosis
 Nephrotic syndrome
 Renal failure (acute or chronic)
 Pregnancy
*

42. Hyponatraemia
Really?
Pseudohyponatraemia
Lipids
Protein
(Glucose)
Is the patient
dehydrated?
Yes
Urine Na >20
mmol/L
Renal Losses
(diuretics,
aldosterone
deficiency,
renal tubular
acidosis,
osmotic
diuresis)
Urine Na <10
mmol/L
Extra-Renal
Losses
(vomiting,
diarrhoea, 3rd
space losses)
Isotonic
saline
No
Is the patient hypervolemic?
No
Euvolemic Hyponatraemia
Urine osmolality
>500 mOsm/kg
SIADH
Water
restriction
Urine osmolality
<500 mOsm/kg
Psychogenic
polydipsia
Water overload
Hypothyroidism
Glucocorticoid
deficiency
Water
restriction
Yes
Heart
failure
Nephrotic
syndrome
Cirrhosis
Renal
Failure
Salt and
water
restriction
*
Richardson A 2010

43. Is the hyponatraemia severe? (Na<125 mmol/L)
Yes
Are there symptoms?
(confusion, ataxia, headache, seizures, obtundation)
Yes
What is the duration of the hyponatraemia?
Acute
(<48 hr)
Emergency
correction with
hypertonic saline
Chronic/Unknown
(>48 hr)
Urgent correction with normal saline
or hypertonic saline until symptoms
resolve thereafter correct slowly
No
Hyponatraemia likely to be chronic
Urgent intervention
unnecessary
Assess volume status
and correct slowly
No
Significant sequelae unlikely
*
Richardson A 2010

44. Hyponatraemia
 Treatment aimed at correcting serum sodium by no
more than 0.5 mmol/L per hour
 Rapid correct of hyponatraemia carries a risk of
osmotic demyelination of pontine and extrapontine
neurons
*

45. Central Pontine Myelinolysis. Fleming
and Babu. NEJM 2008
*

46. Hyponatraemia
 Mrs VD is an 83 yo with dementia, hypertension and type
2 diabetes mellitus. She takes paroxetine (SSRI),
metformin and ramipril. She has been sent in by her GP for
investigation and management of her hyponatraemia
Analyte Result Analyte Result
Na 118 (↓↓↓) U Osm 548
K 5.1 U Na 69
Cl 83 (↓)
HCO3
- 21
Urea 5.1
Creat 83
*

47. Hyponatraemia
Really?
Pseudohyponatraemia
Lipids
Protein
(Glucose)
Is the patient
dehydrated?
Yes
Urine Na >20
mmol/L
Renal Losses
(diuretics,
aldosterone
deficiency,
renal tubular
acidosis,
osmotic
diuresis)
Urine Na <10
mmol/L
Extra-Renal
Losses
(vomiting,
diarrhoea, 3rd
space losses)
Isotonic
saline
No
Is the patient hypervolemic?
No
Euvolemic Hyponatraemia
Urine osmolality
>500 mOsm/kg
SIADH
Water
restriction
Urine osmolality
<500 mOsm/kg
Psychogenic
polydipsia
Water overload
Hypothyroidism
Glucocorticoid
deficiency
Water
restriction
Yes
Heart
failure
Nephrotic
syndrome
Cirrhosis
Renal
Failure
Salt and
water
restriction
Richardson A 2010
*

48. Hypernatraemia
 Normal plasma sodium is 135-145 mmol/L
 By definition, any plasma sodium value above 145
mmol/L is considered to constitute hypernatraemia
 Less common because of the thirst impulse
 Clinical presentation
 Lethargy
 Weakness
 Irritability
 Neuromuscular excitability
 Seizures and coma
*

49. Hypernatraemia
 Aetiology
 Hypovolemic hypernatraemia
 Renal sodium loss
 Diuretics
 Osmotic diuresis
 Extra-renal sodium loss
 Diarrhoea
 Excessive sweating
 Euvolemic hypernatraemia
 Diabetes insipidus
 Hypervolemic hypernatraemia
 Increased oral or IV salt
 Chronic renal failure (during water restriction)
*

50. Hypernatraemia
 Mrs MH, a 79yo female nursing home resident with
mild dementia presents with worsening confusion over
the last 3 days. She has recently been treated with
antibiotics for a urinary tract infection but is otherwise
healthy and on no other medications.
 On examination, she is febrile (38.1oC), HR 90, RR 18
and BP 118/60

51. Hypernatraemia
Analyte Result Analyte Result
Na 165 (↑) U Osm 700
K 4.6 U Na 93
Cl 118 (↑)
HCO3
- 28
Urea 14.6 (↑)
Creat 115 (↑)
*

52. Hypernatraemia
 Hypovolemic hypernatraemia
 Renal sodium loss
 Diuretics
 Osmotic diuresis
 Extra-renal sodium loss
 Diarrhoea
 Excessive sweating
 Euvolemic hypernatraemia
 Diabetes insipidus
 Hypervolemic hypernatraemia
 Increased oral or IV salt
 Chronic renal failure (during water restriction)
*

53. Hypokalaemia
 Normal plasma potassium is 3.5-5.0 mmol/L
 By definition, any plasma potassium value below 3.5
mmol/L is considered to constitute hypokalaemia
 Important to remember that K+ is the major
intracellular cation so there is a major concentration
gradient across the cell membrane
 K+ can be driven into cells by
 ECF alkalosis
 Hormones – insulin, catecholamines, aldosterone
*

54. Hypokalaemia
 90% of the dietary load of K+ is excreted by the
kidneys
 Aldosterone is the single most important factor in
determining K+ excretion
 Clinical presentation
 Muscle weakness, myalgia, muscle cramps
 Constipation
 Flaccid paralysis and hyporeflexia
 ECG changes
 Arrhythmias
*

55. Hypokalaemia
Factitious?
Redistribution into cells?
Excessive potassium losses
Renal losses
Alkalosis
Insulin excess
Catecholamine
Hypokalaemic periodic paralysis
Richardson A 2013
↓ potassium intake?
Dietary
IV fluids
Non-renal losses
Hyperaldosteronism
Corticosteroid therapy
Cushing’s syndrome
Liquorice
Diuretics
RTA
Hypomagnesaemia
Vomiting
Diarrhoea
Laxative abuse
Bowel obstruction
Ureterosigmoidostomy

56. Hypokalaemia
Factitious?
Redistribution into cells?
Excessive potassium losses
Renal losses
Alkalosis
Insulin excess
Catecholamine
Hypokalaemic periodic paralysis
Drip arm?
*
Richardson A 2013
↓ potassium intake?
Dietary
IV fluids
Non-renal losses
Hyperaldosteronism
Corticosteroid therapy
Cushing’s syndrome
Liquorice
Diuretics
RTA
Hypomagnesaemia
Vomiting
Diarrhoea
Laxative abuse
Bowel obstruction
Ureterosigmoidostomy

57. Hypokalaemia
 Mr PR is a 58 yr old male with a history of paranoid
schizophrenia, hypertension and her GP had sent him
in by ambulance for investigation and management of
severe hypokalaemia.
 Medications included olanzepine and an oral
potassium supplement prescribed by his GP.
 Examination was unremarkable and the only
abnormality was a BP of 192/112.
 ECG showed early changes consistent with
hypokalaemia

58. Hypokalaemia
Analyte Result Analyte Result
Na 142 Glu 5.7
K 1.8 (↓↓↓) Mg 1.1
Cl 103 Urine Na 68
HCO3
- 43 (↑) Urine K 33
Urea 3.1
Creat 83

59. Hypokalaemia
Factitious?
Redistribution into cells?
Excessive potassium losses
Renal losses
Alkalosis
Insulin excess
Catecholamine
Hypokalaemic periodic paralysis
Drip arm?
Richardson A 2013
↓ potassium intake?
Dietary
IV fluids
Non-renal losses
Hyperaldosteronism
Corticosteroid therapy
Cushing’s syndrome
Liquorice
Diuretics
RTA
Hypomagnesaemia
Vomiting
Diarrhoea
Laxative abuse
Bowel obstruction
Ureterosigmoidostomy
Mr PR
K 1.8
Bicarb 43
Mg 1.1
Urine K 33

60. Hypokalaemia
 Further history from Mr PR
 He takes a range of herbal supplements including
 Animal adrenal extract
 Black liquorice oil
*

61. Hyperkalaemia
 Normal plasma potassium is 3.5-5.0 mmol/L
 By definition, any plasma potassium value above 5.0
mmol/L is considered to constitute hyperkalaemia
 Clinical presentation
 Often asymptomatic
 Malaise
 Palpitations
 Muscle weakness
 Cardiac arrhythmia or sudden death
*

62. Hyperkalaemia
Factitious?
Redistribution out of
cells?
Renal retention of potassium
Renal failure
Acidosis
Insulin deficiency (DKA)
Catecholamine deficiency ( -blockers)
Hyperkalaemic periodic paralysis
Richardson A 2013
↑ potassium into ECF?
Exogenous – diet, IV fluids
Endogenous – damaged tissues, intravascular
haemolysis, rhabdomyolysis, chemotherapy,
crush injury
Renal tubule
dysfunction
Acute
Chronic
Addison’s disease
Drugs (NSAIDs, ACE inhibitors, -blockers)
Pseudohypoaldosteronism
Tubulointerstitial disease (SLA, amyloidosis,
infection)
RTA
Potassium sparing diuretics (amiloride,
spironolactone)

63. Hyperkalaemia
Factitious?
Redistribution out of
cells?
Renal retention of potassium
Renal failure
Acidosis
Insulin deficiency (DKA)
Catecholamine deficiency ( -blockers)
Hyperkalaemic periodic paralysis
Richardson A 2013
↑ potassium into ECF?
Exogenous – diet, IV fluids
Endogenous – damaged tissues, intravascular
haemolysis, rhabdomyolysis, chemotherapy,
crush injury
Renal tubule
dysfunction
Haemolysis, very high WBC/Plt, drip arm,
long torniquet times, EDTA contamination,
Acute
Chronic
Addison’s disease
Drugs (NSAIDs, ACE inhibitors, -blockers)
Pseudohypoaldosteronism
Tubulointerstitial disease (SLA, amyloidosis,
infection)
Potassium sparing diuretics (amiloride,
spironolactone)
*

64. Hyperkalaemia
 Mr KG is a 78 yr old man who lives alone. He was last
seen 3 days ago and was just found by his son on the
floor of his apartment. He is complaining of pain in
his left hip and is acutely confused.
 He has a history of poorly controlled type 2 diabetes
mellitus, hypertension and osteoarthritis.
 His normal medications are metformin, ramipril and
celebrex.
 His vital signs were HR 96, BP 78/54, RR 34, T38.2
 ECG is consistent with hyperkalaemia

65. Hyperkalaemia
Analyte Result Analyte Result
Na 132 (↓) Glu 32.7 (↑)
K 8.7 (↑↑↑) Arterial pH 7.12 (↓)
Cl 93 (↓)
HCO3
- 8 (↓)
Urea 21.2 (↑)
Creat 160 (↑)

66. Hyperkalaemia
Factitious?
Redistribution out of
cells?
Renal retention of potassium
Renal failure
Acidosis
Insulin deficiency (DKA)
Catecholamine deficiency ( -blockers)
Hyperkalaemic periodic paralysis
Richardson A 2013
↑ potassium into ECF?
Exogenous – diet, IV fluids
Endogenous – damaged tissues, intravascular
haemolysis, rhabdomyolysis, chemotherapy,
crush injury
Renal tubule
dysfunction
Haemolysis, very high WBC/Plt, drip arm,
long torniquet times, EDTA contamination,
Acute
Chronic
Addison’s disease
Drugs (NSAIDs, ACE inhibitors, -blockers)
Pseudohypoaldosteronism
Tubulointerstitial disease (SLA, amyloidosis,
infection)
Potassium sparing diuretics (amiloride,
spironolactone)
*
Mr KG
K 8.7
Bicarb 8
Urea 21.2
Creat 160
Glu 32.7

67. Questions?